Aminophenoxyacetic acid derivatives and pharmaceutical composition containing thereof

ABSTRACT

There is provided an aminophenoxyacetic acid derivative of the following formula (I): 
                         
wherein, R 1 , R 2 , R 3  and R 4  are, independent from each other, alkoxy group, alkyl group or aryl group, etc.; E 1  and E 2  are oxygen atom, sulfur atom, etc.; n is 0 to 5; X and Y are alkylene group, cycloalkylen group, or alkenylen group; Q is phenyl group which may be substituted or benzoyl group, etc, or a pharmaceutically acceptable salt thereof.
 
     These compounds have neuroprotective effects by inducing calbindin D28Kd, one of Ca 2+ -binding proteins.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. application Ser. No.10/394,221, filed Mar. 24, 2003, now U.S. Pat. No. 6,998,401 which is acontinuation of U.S. application Ser. No. 09/581,756, filed Nov. 1,2000, now U.S. Pat. No. 6,559,146, which is a national stage applicationof International Application No. PCT/JP99/05658 filed Oct. 14, 1999,which claims benefit of Japanese Application No. 10-294886, filed Oct.16, 1998.

TECHNICAL FIELD

The present invention relates to novel aminophenoxyacetic acidderivatives and pharmaceutically acceptable salt thereof, which haveneuroprotective effects by inducing or increasing calbindin D28Kd, oneof Ca²⁺-binding proteins, and which are useful in ameliorating andtreating functional and organic disorders in the brain. Morespecifically, the present invention relates to therapeutic and improvingagents for the alleviation or treatment of symptoms due to variousischemic disorders in the brain such as sequelae of cerebral infarction,sequelae of intracerebral hemorrhage, sequelae of cerebralarteriosclerosis and so on, and symptoms of organic brain disorder suchas senile dementia, sequelae of head trauma, sequelae of surgical brainoperation, Alzheimer's disease, Parkinson's disease, amyotrophic lateralsclerosis and so on.

BACKGROUND ART

It is generally considered that the pathogenesis of progressive, delayeddeath of nerve cells, observed in cerebral injury and cerebrovasculardisease such as intracerebral hemorrhage, transient ischemia attack, andcerebral infarction, is mainly caused by a rise in intracellular Ca²⁺concentration due to various factors related to signal transductions.Such factors related to signal transduction include, for example,abnormal activation of glutamate receptors due to excessive releaseglutamate, that is, an excitatory neurotransmitter, abnormal activationof ion channels, and excessive production of reactive oxygenspecies/free radicals. [F. B. Meyer, Brain Res. Rev., 14, 227 (1989); E.Boddeke et al., Trends Pharmacol. Sci., 10, 397 (1989); J. M. McCall etal., Ann. Rep. Med. Chem., 27, 31 (1992)].

From these points of view, medicaments for preventing or suppressing theneuronal cell death, such as glutamate receptor antagonists, calciumchannel blockers, antioxidants and so on have been developed. However,these clinically used medicaments suppress only a few pathways relatedto increase of the cellular Ca²⁺ concentration, and are not sufficientfor preventing or suppressing the neuronal cell death.

On the contrary, calbindin D28Kd, one of Ca²⁺-binding proteins andmainly distributed in friable site of the brain against ischemicdisease, is reported to possess buffering effects for a rise incytotoxic intracellular Ca²⁺ concentration. [A. M. Lacopino et al.,Neurodegeneration, 3, 1 (1994); M. P. Mattson et al., Neuron, 6, 41(1991)]

Accordingly, it is expected to achieve sufficient neuroprotectiveeffects against the increase of intracellular Ca²⁺ concentration causedby any kinds of pathways if calbindin D28Kd, one of the Ca²⁺-bindingproteins per se, can be supplied in a living body. That is, it isexpected that medicaments containing calbindin D28Kd would be effectivetherapeutic and improving agents for the allevivation or treatment ofsymptoms due to various ischemic disorders in the brain such as sequelaeof cerebral infarction, sequelae of intracerebral hemorrhage, sequelaeof cerebral arteriosclerosis and so on, and symptoms of organic braindisorder such as senile dementia, sequelae of head trauma, sequelae ofsurgical brain operation, Alzheimer's disease, Parkinson's disease,amyotrophic lateral sclerosis and so on.

However, because calbindin D28Kd is unstable macromolecular proteinhaving 28 Kd (kilo dalton) of molecular weight, it is difficult to beadministered directly into a site in the central nervous system of aliving body in view of pharmacological and pharmaceutical standpoints.

On the other hand, the lower molecular compounds having effect oninduction of the calbindin D28Kd can be easily prepared into the variouskinds of pharmaceutical compositions by the conventional techniques.Thus, these lower molecular compounds are expected to induce thecalbindin D28Kd after administration in to a body, and to possessbuffering action against the increase of the cellular Ca²⁺concentration. That is, these lower compounds can be effective compoundsfor improving and treating cerebral functional and organic disorders.

Under these circumstances, the objective of the present invention is toprovide the lower molecular weight compounds having neuroprotectiveeffect by inducing the calbindin D28Kd, one of Ca²⁺-binding proteins, oflow toxicity in suitable preparations of pharmaceutical compositionssuch as intravenous injectable solution.

The further purpose of the present invention is to provide thetherapeutic and improving agents for the allevivation or treatment ofsymptoms due to various ischemic disorders in the brain such as sequelaeof cerebral infarction, sequelae of intracerebral hemorrhage, sequelaeof cerebral arteriosclerosis and so on, and symptoms of organic braindisorder such as senile dementia, sequelae of head trauma, sequelae ofsurgical brain operation, Alzheimer's disease, Parkinson's disease,amyotrophic lateral sclerosis and so on.

DISCLOSURE OF THE INVENTION

As one aspect of the present invention, it is providedaminophenoxyacetic acid derivatives represented by the following formula(I):

wherein:

R¹, R², R³ and R⁴ are, independent from each other, hydrogen atom;halogen atom; hydroxy group; alkoxy group which may be substituted;alkyl group which may be substituted; aryl group which may besubstituted; or aralkyl group which may be substituted;

R⁵, R⁶, R⁷ and R⁸ are, independent from each other, hydrogen atom; alkylgroup which may be substituted; aryl group which may be substituted; oraralkyl group which may be substituted;

E¹ is oxygen atom; sulfur atom; or group —NR⁹— (in which, R⁹ is hydrogenatom; alkyl group which may be substituted; aryl group which may besubstituted; or aralkyl group which may be substituted);

E² is oxygen atom; sulfur atom; or group —NR¹⁰— (in which, R¹⁰ ishydrogen atom; alkyl group which may be substituted; aryl group whichmay be substituted; or aralkyl group which may be substituted);

n is 0 to 5

X and Y are, independent from each other, connecting bond; alkylenegroup which may be substituted by hydroxyl group, carboxyl group, oxogroup or morpholinyl group; cycloalkylene group; alkenylene group whichmay be substituted by lower alkyl group; —NHCO—; —CONH—; or —SO₂—; or—X-Y—represents —CON(CH₃)—;

Q is hydrogen atom; naphthyl group; phenyl group which may besubstituted; phenoxy group which may be substituted; benzoyl group whichmay be substituted; pyridyl group which may be substituted; quinolylgroup which may be substituted; isoquinolyl group which may besubstituted; or benzimidazolyl group which may be substituted; (providedthat one of E¹ and E² represent either oxygen atom or sulphur atom thenthe other one of E¹ and E² represent neither oxygen atom nor sulfur atomat the same time, and in the case of E¹ is nitrogen atom and E² isoxygen atom, or in the case of E¹ is oxygen atom and E² is nitrogenatom, all of the groups of R¹, R², R³ and R⁴ do not represent methylgroup at the same time), or pharmaceutically acceptable salts thereof.

More specifically, the present invention provides the aminophenoxyaceticacid derivatives of the formula (I), in which;

-   -   1. R¹, R², R³ and R⁴ are, independent from each other, hydrogen        atom; halogen atom; alkoxy group; or alkyl group which may be        substituted; R⁵ is hydrogen atom or alkyl group which may be        substituted; E¹ is —NH—; and E² is oxygen atom,    -   2. E¹ is —NH—; E² is oxygen atom; either the case in which X is        connecting bond and Y is group —CONH—, or the other in which X        is the group —CONH— and Y is connecting bond; Q is phenyl group        which may be substituted, and    -   3. E¹ and E² are —NH—; X and Y are connecting bond; Q is phenyl        group which may be substituted,        or pharmaceutically acceptable salts thereof.

According to the present inventor's investigations, it is confirmed thatthe aminophenoxyacetic acid in low concentration represented by theformula (I) effectively induced the calbindin D28Kd and possessedexcellent neuroprotective effect accordingly. Further, these compoundsare also confirmed to have high safety margin, and are suitable forpreparation of various kinds of pharmaceutical compositions.

Therefore, the present invention provides the calbindin D28Kd, inducingagent containing aminophenoxyacetic acid derivatives represented by theformula (I) or pharmaceutically acceptable salts thereof as an activeingredient, as another embodiment.

As still a further embodiment, the present invention provides animproving and therapeutic agent for the cerebral functional and organicdisorders containing aminophenoxyacetic acid derivatives represented bythe formula (I) or pharmaceutically acceptable salt thereof, as anactive ingredient.

Although lower molecular weight compounds, the aminophenoxyacetic acidderivatives of the formula (I) express the neuroprotective effect byinducing the calbindin D28Kd after administration into a living body.

Accordingly, as still another embodiment, the present invention providesa method for selecting a neuroprotective compound by measurement ofinducing capability of calbindin D28Kd, which is Ca²⁺-binding protein.

As still another embodiment, the present invention providesneuroprotective compounds to induce the calbindin D28Kd, one ofCa²⁺-binding proteins.

As still a further embodiment, the present invention providestherapeutic and improving agents containing compounds havingneuroprotective effect by inducing the calbindin D28Kd, against cerebralfunction disorders due to various ischemic disorders such as cerebralinfarction, intracerebral hemorrhage and cerebral arteriosclerosis.

As still a further embodiment, the present invention providestherapeutic and improving agents containing compounds havingneuroprotective effect by inducing calbindin D28Kd, for cerebral organicdisorders such as senile dementia, cerebral injury, sequela of cerebralsurgical operation, Alzheimer's disease, Parkinson's disease, andamyotrophic lateral sclerosis.

As a preferred embodiment, the present invention provides theaminophenoxyacetic acid derivatives represented by the formula (I) orpharmaceutically acceptable salt thereof is the pharmaceuticalcomposition containing the compounds having neuroprotective effect byinducing the calbindin D28Kd.

BEST MODE FOR CARRYING OUT THE INVENTION

The aminophenoxyacetic acid derivatives of the present invention includeaminophenoxyacetic acids, aminoanilinoacetic acids,aminothiophenoxyacetic acids, oxyanilinoacetic acids andthioanilioacetic acids. Therefore, “aminophenoxyacetic acid derivatives”in this specification include all the derivatives stated above as longas not stated otherwise.

In the aminophenoxyacetic acid derivatives of the formula (I) providedby the present invention with reference to various substitution group ofR¹ to R¹⁰, “halogen atom” includes fluorine atom, chlorine atom andbromine atom.

The term “alkoxy group” stands for a straight-chained orbranched-chained C₁-C₅ alkoxy group, and may include, for example,methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy,tert-butoxy and the like.

The term “alkyl group which may be substituted” stands for astraight-chained or branched-chained C₁-C₅ alkyl group which may behalogen-substituted, and may include, for example, methyl, ethyl,propyl, trifluoromethyl group, and the like.

The “aryl”, a part of the term “aryl group which may be substituted”,stands for C₄-C₁₄ aryl group or heteroaryl group which may contain oneor more of hetero ring atom(s) such as nitrogen and oxygen atom(s).Examples of the preferred “aryl” include phenyl, pyridyl and naphthyl.The suitable substituents of said aryl group include halogen atom suchas fluorine atom, chlorine atom and bromine atom; hydroxy group; astraight-chained or branched-chained C₁-C₅ alkoxy group such as methoxyand ethoxy group; and a straight-chained or branched-chained C₁-C₅ alkylgroup which can be substituted by halogen atom such as methyl, ethyl,propyl and trifluoromethyl.

The “aralkyl”, a part of the term “aralkyl group which may besubstituted”, stands for C₅-C₁₂ aralkyl group or heteroarylalkyl group,which may contain one or more of hetero ring atom such as nitrogen andoxygen atom(s). The examples include benzyl, phenethyl, pyridylmethyl,and pyridylethyl. The suitable substituents of said aralkyl groupinclude halogen atoms such as fluorine atom, chlorine atom and bromineatom; hydroxy group; a straight-chained or branched-chained C₁-C₅ alkoxygroup such as ethoxy group; and a straight-chained or branched-chainedC₁-C₅ alkyl group which may be substituted by halogen atom such asmethyl, ethyl, propyl and trifluoromethyl.

The “alkylene”, a part of the term “alkylene group which may besubstituted by hydroxyl group”, refers to the substituents X and Y, andpreferably represents a straight-chained or branched-chained C₁-C₆alkylene group such as methylene, methylmethylene, ethylene,trimethylene, tetramethylene, cyclopropylmethylene and the like.

The term “cycloalkylene” preferably stands for C₃-C₆ cycloalkylene andmay include 1,1-cyclopropylene, 1,2-cyclo-propylene, 1,1-cyclobutylene,1,1-cyclopentylene, 1,1-cyclo-hexylene and the like. Among them,1,1-cyclopropylene and 1,2-cyclopropylene are more preferable.

The “alkenylene”, a part of the term “alkenylene group which may besubstituted by lower alkyl group”, may include C₂-C₄ alkenylene such asvinylene, and butadiene and vinylene is preferably used. The lower alkylgroup, which is substituent of alkylene group, may be methyl, ethyl,propyl, isopropyl and the like.

The suitable substituents represented as “Q” for “phenyl group which maybe substituted”, “phenoxy group which may be substituted”, “benzoylgroup which may be substituted”, “pyridyl group which may besubstituted”, “quinolyl group which may be substituted”, “isoquinolylgroup which may be substituted” and “benzimidazolyl group which may besubstituted”, may include a halogen atom such as a fluorine atom, achlorine atom and a bromine atom; a hydroxyl group; a straight-chainedor branched-chained C₁-C₅ alkoxy group such as methoxy, ethoxy group andso on. Furthermore, these substituents may also include astraight-chained or branched-chained C₁-C₅ alkyl group which may besubstituted by halogen atom such as fluorine atom, chlorine atom andbromine atom. The examples include methyl, ethyl, propyl,trifluoromethyl and the like. Still further, these substituents includea carboxyl group, a carbamoyl group and an amino group.

The term “connecting bond” with reference to “X” and “Y” means directbond. Therefore, if “X” and/or “Y” are connecting bond, two adjacentsubstituents of “X” and/or “Y” are connected directly, and thesesubstituents do not exist as “X” and/or “Y”.

It is understood that when the aminophenoxyacetic acid derivatives ofthe formula (I) of the present invention exist in the isomer forms, eachisomers per se, as well as the isomeric mixture, shall be included inthe compounds of the present invention. Namely, the structural isomersmay exist due to the substituents on the benzene ring. Furthermore,optical isomers may exist due to the asymmetric carbon atom of thehydroxy substituted “X” or “Y” of alkylene group. These isomers shall beincluded within the scope of the compounds of the present invention.

The aminophenoxyacetic acid derivatives of the formula (I) include thecompounds (Ia), (Ib) and. (Ic) obtained by the synthetic processmentioned latter. For example, these compounds may be prepared by thefollowing.

The compound (IV), obtained by the reaction of the compound (II) withthe ester compound (III), is hydrolyzed to convert into carboxylic acidderivative (V). The obtained compound (V) is then converted into amidecompound (VII) by the condensation reaction with the compound (VI).Further, the protecting group in the compound (VII) thus obtained isremoved to obtain compound (Ia), the compound of formula (I) of thepresent invention, in which n is 0, X and Y is are each a connectingbond and Q is a hydrogen atom (Process 1).

The compound (Ib) can be obtained by reacting the compound (Ia) with thecompound (VIII) (Process 2).

Furthermore, the compound (Ic) can be obtained by reacting the compound(Ia) with the compound (IX) (Process 3).

Each process will be further illustrated by the following reactionscheme.

wherein R¹ to R⁸, E¹ and E² have the same definitions as above, and R¹¹is alkyl group which may be substituted, aryl group which may besubstituted; aralkyl group which may be substituted; tert-butoxycarbonylgroup; ethoxycarbonyl group; acetyl group; benzyloxycarbonyl group;p-methoxybenzyloxycarbonyl group; R¹² is a straight-chained orbranched-chained C₁-C₅ alkyl group; L¹ is leaving group which can easilybe replaced with amino, hydroxy and mercapto group; P is benzyl group,tert-butoxycarbonyl group, ethoxycarbonyl group; acetyl group;benzyloxycarbonyl group; p-methoxybenzyloxycarbonyl group.

According to this process 1, the compound (Ia) can be obtained from theknown starting compound (II).

Namely, for the first step, the compound (II) is reacted with 1.0 to 1.5mole equivalent of ester compound (III) in the inert solvent, and ifnecessary in the presence of the base, under stirring at −20° C. to 150°C., preferably at 0° C. to 100° C.

The inert solvent to be used in the reaction may be benzene, toluene,tetrahydrofuran, dioxane, dimethyformamide, dimethyl sulfoxide,acetonitrile, acetone, methanol, ethanol, isopropyl alcohol, tert-butylalcohol, ethylene glycol and the like.

The base to be used in the above reaction may be an organic base such astriethylamine, diisopropylethylamine, pyridine and the like, or aninorganic base such as sodium, sodium hydride, potassium, potassiumhydride, sodium ethoxide, potassium tert-butoxide, sodium carbonate,potassium carbonate, cesium carbonate, cesium fluoride, sodiumbicarbonate, potassium bicarbonate and the like. These organic base andinorganic base may be used in combination, and sodium iodide ortetrabutylammonium iodide can be added in the reaction mixture.

The substituent “L¹” in the ester compound (III) may be the leavinggroup which can easily be replaced with amino, hydroxy and mercaptogroup, and examples include halogen atom such as chlorine atom, bromineatom, iodide atom; alkylsulfonyloxy group such as methanesulfonyloxygroup; arylsulfonyloxy group such as p-toluenesulfonyloxy group,3-nitrobenzenesulfonyloxy group and the like.

The compounds (II) and (III) to be used in this reaction are commercialavailable ones, or can easily prepared by the known methods.

The compound (II) and compound (III) to be used in this reaction can becommercially available and known compounds, or can be easily preparedfrom known compounds by using common methods.

Examples of the compound (II) include 4-(tert-butoxycarbonylamino)phenol4-(tert-butoxycarbonylamino)-2,3,5-trimethylphenol,4-(tert-butoxycarbqnylamino)-2-chloro-3,5,6-tri-methylphenol,4-(tert-butoxycarbonylamino)-2,3,6-trimethylphenol,4-(tert-butoxycarbonylamino)-2,3-dimethylphenol,4-(tert-butoxy-carbonylamino)-2,5-dimethylphenol,2-(tert-butoxycarbonylamino)-4,6-dimethylphenol,5-(tert-butoxycarbonylamino)-2-methoxyphenol,5-(tert-butoxycarbonylamino)-4-chloro-2-methoxyphenol,4-(tert-butoxycarbonylamino)-2,6-dichlorophenol,4-(tert-butoxycarbonyl-amino)-2,3,5,6-tetramethylaniline,4-methoxy-2-methylaniline,4-(tert-butoxycarbonylamino)-2,5,-dimethylaniline,2-(tert-butoxy-carbonylamino)-4,5-dimethylaniline,3-(tert-butoxycarbonylamino)-2,4,6-trimethylaniline,4-(tert-butoxycarbonylamino)-2,5-di-chloroaniline,4-(tert-butoxycarbonylamino)-2,6-dichloroaniline,2-(tert-butoxycarbonylamino)-3,4-dichloroaniline,4-(tert-butoxy-carbonylamino)-2-methoxy-5-methylaniline,4-(tert-butoxycarbonyl-amino)-2,5-dimethoxyanilie,4-(benzyloxycarbonylamino)phenol,4-(benzyloxycarbonylamino)-2,3,5-trimethylphenol,4-(benzyloxycarbonylamino)-2-chloro-3,5,6-trimethylphenol,4-(benzyloxycarbonylamino)-2,3,6-trimethylphenol,4-(benzyloxycarbonylamino)-2,3-dimethylphenol,4-(benzyloxycarbonylamino)-2,5-dimethylphenol,2-(benzyloxycarbonylamino)-4,6-dimethylphenol,5-(benzyloxycarbonylamino)-2-methoxyphenol,5-(benzyloxycarbonylamino)-4-chloro-2-methoxyphenol,4-(benzyloxycarbonylamino)-2,6-dichlorophenol,4-(benzyloxycarbonylamino)-2,3,4,6-tetramethylaniline,4-(benzyloxycarbonylamino)-2, 5-dimethylaniline,2-(benzyloxycarbonylamino)-4,5-dimethylaniline,3-(benzyloxycarbonylamino)-2,4,6-trimethylaniline,4-(benzyloxycarbonylamino)-2,5-dichloroaniline,4-(benzyloxycarbonylamino)-2,6-dichloroaniline,2-(benzyloxycarbonylamino)-3,4-dichloroaniline,4-(benzyloxycarbonylamino)-2-methoxy-5-methylaniline,4-(benzyloxycarbonylamino)-2, 5-dimethoxyaniline and so on.

The ester compound of the formula (III) includes, for example, ethylbromoacetate, ethyl 2-bromopropionate, ethyl 2-bromo-2-methylpropionate,and so on.

Then, the obtained compound (IV) is hydrolyzed to convert intocarboxylic acid derivative (V) by the common methods, and the resultantcarboxylic acid derivative of the formula (V) is further converted intoamide derivative (VII) by reaction with the compound (VI).

The compound (VI) to be used for the reaction with the compound (V) isknown compound as described in J. Med. Chem., 36, 3707 (1993) [R. H.Mach et al.], or can be easily prepared by the methods described in EP0184257 A1 [R. A. Stokbroekx, et al.].

The reaction conditions of this amidation reaction may vary according tothe methods described in “Compendium for Organic Synthesis”(wiley-Interscience: A Division of John Wiley & Sons Ltd.). For example,the compound (V) is treated optionally in the presence of an organic oran inorganic base with diethyl cyanophosphonate (DEPC),diphenylphosphoryl azide (DPPA), dicyclohexylcarbodiimide (DCC),1-ethyl-3-(3-dimethylamino-propyl)carbodiimide hydrochloride,2-iodo-1-methylpyridinium iodide orbenzotriazol-1-yloxy-tris(dimethylamino)phosphonium hexafluorophosphate(BOP Reagent), and then reacted with compound (VI) to obtain the amidecompound (VII). Furthermore, the compound (V) is converted into theactivated ester compound such as acid halide, symmetric acid anhydride,or the mixture acid anhydride, then reacted with the compound (VI) toobtain the amide compound (VII).

The compound (VII) thus obtained is converted into theaminophenoxyacetic acid derivatives of the formula (Ia), the compound ofthe present invention, by the removal reaction of the protecting groupon the nitrogen atom of the amide compound (VII).

This reaction may vary depend on the protecting group on the nitrogenatom of the compound (VII). For example, the compound (VII) is treatedwith acids such as trifluoroacetic acid, hydrogen chloride, hydrogenbromide, or sulfuric acid in an inert solvent such as benzene, toluene,acetonitrile, tetrahydrofuran, dioxane, chloroform, carbontetrachloride, and the like. Furthermore, the removal of the protectinggroup may also be carried out by hydrogenolysis of the compound (VII)under 1 to 5 atm of hydrogen, in the presence of a catalyst such aspalladium-carbon, palladium hydroxide, platinum, or platinum oxide, inan inert solvent such as methanol, ethanol, isopropyl alcohol, ethylacetate or acetic acid.

Although each compounds obtained in the above process 1 may be used forthe next reaction without further purification, it can also be usedafter further purification in conventional manner such asrecrystallization or column chromatography and so on if necessary.

wherein R¹ to R⁸, E¹, E², n, X and Y have the same definitions as above;and Q′ is phenyl group which may be substituted, phenoxy group which maybe substituted, benzoyl group which may be substituted, pyridyl groupwhich may be substituted, quinolyl group which may be substituted,isoquinolyl group which may be substituted, or benzimidazolyl groupwhich may be substituted; L² is leaving group which can be easilyreplaced with the amino group.

According to this process 2, the aminophenoxyacetic acid of the formula(Ib) of the present invention can be obtained by reacting the compound(Ia), obtained in the process 1 mentioned above, with the compound(VIII).

The compound (Ia) is reacted with 1.0 to 1.5 mole equivalent of thecompound (VIII) in the inert solvent such as benzene, toluene,acetonitrile, ether, tetrahydrofuran, dioxan, methylene chloride,chloroform, carbon tetrachloride, dimethyl-formamide, and dimethylsulfoxide in the presence of the base, at −50° C. to 120° C., preferablyat −20° C. to 50° C.

The base to be used in the reaction may be an organic base such astriethylamine, pyridine, diisopropylethylamine and the like, or aninorganic base such as sodium carbonate, potassium carbonate, cesiumcarbonate, sodium bicarbonate, potassium bicarbonate, cesium fluoride,sodium hydride and the like. Sodium iodide or tetrabutylammonium iodidecan be added in the reaction mixture.

The substituent “L²” in the compound (VIII) is the leaving group, whichcan easily be replaced by amino group, and examples include halogen atomsuch as chlorine atom, bromine atom; alkylsulfonyloxy group such asmethanesulfonyloxy group; arylsulfonyloxy group such asp-toluenesulfonyloxy group and the like.

In this process 2, the aminophenoxyacetic acid of the formula (Ib) canbe produced as well.

wherein R¹ to R⁸, E¹, E², Q and L² have the same definitions aspreviously mentioned, and p is 0 to 3.

According to this process 3, the aminophenoxyacetic acid of the formula(Ic) of the present invention can be obtained from the reaction of thecompound (Ia), obtained in the process 1 mentioned above, with thecompound (IXa) or the compound (IXb).

For example, the compound (Ia) is reacted with 0.9 to 1.5 moleequivalent of the compound (IXa) or (IXb) in an inert solvent at fromroom temperature to about 200° C., preferably at about 50° C. to about150° C., to produce the aminophenoxyacetic acid of the formula (Ic).

The inert solvent to be used in the reaction may be benzene, toluene,tetrahydrofuran, diethyl ether, ethylene glycol dimethyl ether, dioxane,dimethyformamide, dimethyl sulfoxide, acetonitrile, methanol, ethanol,isopropyl alcohol, t-butyl alcohol, ethylene glycol and the like.

Examples of the compound (IXa) include epibromohydrin, epichlorohydrin,(R)-epichlorohydrin, (S)-epichlorohydrin and the like, and examples ofthe compound (IXb) include glycidyl tosylate, (R)-glycidyl tosylate,(S)-glycidyl tosylate, (R)-glycidyl 3-nitrobenzensulfonate, (S)-glycidyl3-nitrobenzen-sulfonate, (R)-glycidyl 4-nitrobenzoate, (S)-glycidyl4-nitro-benzoate, gylcidyltrimethylammonium chloride and the like.

In this process 3, the aminophenoxyacetic acid of the formula (Ic) canbe produced as well.

The aminophenoxyacetic acid derivatives of the formula (I) thus obtainedmay be isolated and purified in conventional manner, such asrecrystallization; column chromatography and the like.

Further, each isomers contained in the compounds of the formula (I) ofthe present invention can be obtained by resolution of the isomericmixture of these compounds by the conventional methods, such asrecrystallization, column chromatography, HPLC, and the like, or byusing optically active reagents.

The compounds of the present invention represented by the formula (I)may be used in the form of free bases or suitable pharmaceuticallyacceptable acid addition salts thereof. The pharmaceutically acceptablesalts can be obtained by treating the compound (I) with an inorganicacid or an organic acid in suitable solvent. Examples of the inorganicacid include hydrochloric acid, sulfuric acid, nitric acid, phosphoricacid, periodic acid and the like. Further, examples of the organic acidinclude formic acid, acetic acid, butyric acid, oxalic acid, malonicacid, propionic acid, valeric acid, succinic acid, fumaric acid, maleicacid, tartaric acid, citric acid, malic acid, benzoic acid,p-toluenesulfonic acid, methanesulfonic acid and the like.

The aminophenoxyacetic acid of the present invention represented by theformula (I) or pharmaceutically acceptable salts thereof shows lowtoxicity and may be administered per se. However, it may be converted inthe form of pharmaceutically acceptable composition with theconventionally pharmaceutically acceptable carriers for improvement ortreatment of ischemic diseases.

The dosage forms may include oral formulations such as capsules, tabletsor parenteral formulations such as injection solution containing thecompound of the formula (I) per se, or using the conventionalexcipients. For example, the capsules can be prepared by mixing thecompound of the formula (I) in powder form with a suitable excipientsuch as lactose, starch or derivatives thereof or cellulose derivatives,and then filled in gelatin capsules.

Also, the tablets can be prepared by mixing the active ingredients withthe above-mentioned excipients, binders such as sodiumcarboxymethylcellulose, alginic acid or gum arabic and water, then ifnecessary, making the resultant mixture into granules. Then, it may befurther mixed with lubricant such as talc or stearic acid, andcompressed into tablet by mean of common tableting machine.

Injectable formulations for parenteral route also can be prepared bydissolving the compound of the formula (I) or salts thereof in steriledistilled solution or sterile physiological saline solution withsolution adjuvant, and filling it into ample. A stabilizer or buffer canbe used in the injectable solution, and the injectable formulation maybe administered intravenously or by dripping.

In administration of the compound of the formula (I) which possessneurocytic protecting effect based on induction of calbindin D28Kd, oneof Ca²⁺-bindind proteins, the therapeutically effective dosage forimproving cerebral functional and organic disorders is not particularlylimited and may vary depending on the various kinds of factors. Thesefactors may be the patient's condition, the severity of the disease,age, existence of a complication, administration route, formulation, aswell as number of times for administration.

A usual recommended daily dose for oral administration is within therange of 0.1-1,000 mg/day/person, preferably 1-500 mg/day/person, whilea usual recommended daily dose for parenteral administration is withinthe range of 1/100 to 1/2 based on dose of the oral administration.These doses also may vary depending on age, as well as the patient'scondition.

EXAMPLES

The present invention is illustrated in more detail by way of thefollowing examples, but it is to be noted that the present invention isnot limited by these Examples in any way.

The compound numbers in the following examples are identical to those inthe Table mentioned later.

Example 12-(4-Amino-2,3,5-trimethylphenoxy)-N-methyl-N-(4-piperidinyl)acetamide(1)

A solution of 1.86 g of2-[4-(tert-butoxycarbonylamino)-2,3,5-trimethylphenoxy]acetic acid, 1.43g of 1-(tert-butoxycarbonyl)-4-methylaminopiperidine, 2.94 g ofbenzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate(BOP Reagent) and 1.26 ml of triethylamine in 30 ml of dimethylformamidewas stirred over night at room temperature. Then, 15 ml of saturatedsodium hydrogen carbonate solution was added to the reaction mixture andthe mixture was extracted with ethyl acetate. The extract was washedwith brine, dried and concentrated under reduced pressure to give aresidue. The obtained residue was dissolved in 30 ml of methylenechloride, and to this solution was added 7.5 ml of trifluoroacetic acidat 0° C., then the mixture was stirred for 2 hours at room temperature.After removal of the solvent, the resultant residue was purified bysilica gel column chromatography (methylene chloride:methanol=12:1) togive 1.52 g (81%) of the above-mentioned compound (1).

Example 22-(4-Amino-2,3,5-trimethylphenoxy)-N-methyl-N-(4-piperidinyl)propamide(2)

The title compound (2) was obtained from2-[4-(tert-butoxycarbonylamino)-2,3,5-trimethylphenoxylpropionic acidand 1-(tert-butoxycarbonyl)-4-methylaminopiperidine by the same manneras the Example 1.

Example 32-(4-Amino-2,3,5-trimethylphenoxy)-2-methyl-N-methyl-N-(4-piperidinyl)propamide(3)

The title compound (3) was obtained from2-[4-(tert-butoxycarbonylamino)-2,3,5-trimethylphenoxy]-2-methylpropionicacid and 1-(tert-butoxycarbonyl)-4-methylaminopiperidine by the samemanner as the Example 1.

Example 42-(2-Amino-4,6-dimethylphenoxy)-N-methyl-N-(4-piperidinyl)acetamide (4)

The title compound (4) was obtained from2-[2-(tert-butoxycarbonylamino)-4,6-dimethylphenoxy)acetic acid and1-(tert-butoxycarbonyl)-4-methylaminopiperidine by the same manner asthe Example 1.

Example 52-(4-Amino-2,3,6-trimethylphenoxy)-N-methyl-N-(4-piperidinyl)acetamide(5)

The title compound (5) was obtained from 2-[4-(tert-butoxycarbonylamino)-2,3,6-trimethylphenoxy]acetic acid and1-(tert-butoxycarbonyl)-4-methylaminopiperidine by the same manner asthe Example 1.

Example 62-(5-Amino-2-methoxyphenoxy)-N-methyl-N-(4-piperidinyl)acetamide (6)

The title compound (6) was obtained from2-[5-(tert-butoxycarbonylamino)-2-methoxyphenoxy]acetic acid and1-(tert-butoxy-carbonyl)-4-methylaminopiperidine by the same manner asthe Example 1.

Example 72-(5-Amino-2-methoxyphenoxy)-N-ethyl-N-(4-piperidinyl)acetamide (7)

The title compound (7) was obtained from2-[5-(tert-butoxycarbonylamino)-2-methoxyphenoxy]acetic acid and1-(tert-butoxycarbonyl)-4-ethylaminopiperidine by the same manner as theExample 1.

Example 82-(5-Amino-4-chloro-2-methoxyphenoxy)-N-ethyl-N-(4-piperidinyl)acetamide(8)

The title compound (8) was obtained from2-[5-(tert-butoxycarbonylamino)-4-chloro-2-methoxyphenoxy]acetic acidand 1-(tert-butoxycarbonyl)-4-ethylaminopiperidine by the same manner asthe Example 1.

Example 92-(4-Amino-2-chloro-3,5,6-trimethylphenoxy)-N-ethyl-N-(4-piperidinyl)acetamide(9)

The title compound (9) was obtained from2-[4-(tert-butoxycarbonylamino)-2-chloro-3,5,6-trimethylphenoxy]aceticacid and 1-(tert-butoxycarbonyl)-4-ethylaminopiperidine by the samemanner as the Example 1.

Example 102-(4-Amino-2,3,5,6-tetramethylanilino)-N-methyl-N-(4-piperidinyl)acetamide(10)

The title compound (10) was obtained from2-[4-(tert-butoxycarbonylamino)-2,3,5,6-tetramethylanilino acetic acidand 1-(tert-butoxycarbonyl)-4-methylaminopiperidine by the same manneras the Example 1.

Example 11 2-(4-Amino-2,3,5-trimethylphenoxy)-N-(4-piperidinyl)acetamide(11)

The title compound (11) was obtained from2-[A-(tert-butoxycarbonylamino)-2,3,5-trimethylphenoxy]acetic acid and1-(tert-butoxycarbonyl)-4-aminopiperidine by the same manner as theExample 1.

Example 12 2-(4-Amino-2,3,5-trimethylphenoxy)-N-(4-piperidinyl)propamide(12)

The title compound (12) was obtained from2-[4-(tert-butoxycarbonylamino)-2,3,5-trirmethylphenoxy)propionic acidand 1-(tert-butoxycarbonyl)-4-aminopiperidine by the same manner as theExample 1.

Example 132-(4-Amino-2,3,5-trimethylphenoxy)-2-methyl-N-(4-piperidinyl-propamide(13)

The title compound (13) was obtained from2-[4-(tert-butoxycarbonylamino)-2,3,5-trimethylphenoxy]-2-methylpropionicacid and 1-(tert-butoxycarbonyl)-4-aminopiperidine by the same manner asthe Example 1.

Example 142-(4-Amino-2,3,5-trimethylphenoxy)-N-ethyl-N-(4-piperidinyl)acetamide(14)

The title compound (14) was obtained from2-[4-(tert-butoxycarbonylamino)-2,3,5-trimethylphenoxy]acetic acid and1-(tert-butoxycarbonyl)-4-ethylaminopiperidine by the same manner as theExample 1.

Example 152-(4-Amino-2,3,5-trimethylphenoxy)-N-ethyl-N-(4-piperidinyl)propamide(15)

The title compound (15) was obtained from2-[4-(tert-butoxycarbonylamino)-2,3,5-trimethylphenoxylpropionic acidand 1-(tert-butoxycarbonyl)-4-ethylaminopiperidine by the same manner asthe Example 1.

Example 162-(4-Amino-2-chloro-3,5,6-trimethylphenoxy)-N-methyl-N-(4-piperidinyl)acetamide(16)

The title compound (16) was obtained from2-[4-(tert-butoxycarbonylamino)-6-chloro-2,3,5-trimethylphenoxy]aceticacid and 1-(tert-butoxycarbonyl)-4-methylaminopiperidine by the samemanner as the Example 1.

Example 172-(4-Amino-2-chloro-3,5,6-trimethylphenoxy)-N-(4-piperidinyl)acetamide(17)

The title compound (17) was obtained from2-[4-(tert-butoxycarbonylamino)-6-chloro-2,3,5-trimethylphenoxy]aceticacid and 1-(tert-butoxycarbonyl)-4-aminopiperidine by the same manner asthe Example 1.

Example 182-(4-Amino-2,3,5,6-tetramethylanilino)-N-ethyl-N-(4-piperidinyl)acetamide(18)

The title compound (18) was obtained from2-[4-(tert-butoxycarbonylamino)-2,3,5,6-tetramethylanilino]acetic acidand 1-(tert-butoxycarbonyl)-4-ethylaminopiperidine by the same manner asthe Example 1.

Example 192-(4-Amino-2,3,5,6-tetramethyl-N-methylanilino)-N-methyl-N-(4-piperidinyl)acetamide(19)

The title compound (19) was obtained from2-[4-(tert-butoxycarbonylamino)-2,3,5,6-tetramethyl-N-methylanilino]aceticacid and 1-(tert-butoxycarbonyl)-4-methylaminopiperidine by the samemanner as the Example 1.

Example 202-(4-Amino-2,3,5,6-tetramethylanilino)-N-methyl-N-(4-piperidinyl)propamide(20)

The title compound (20) was obtained from2-[4-(tert-butoxycarbonylamino)-2,3,5,6-tetramethylanilino]propionicacid and 1-(tert-butoxycarbonyl)-4-methylaminopiperidine by the samemanner as the Example 1.

Example 212-[4-(Tert-butoxycarbonylamino)-2,3,5,6-tetramethyl-anilino]-N-(4-piperidinyl)acetamide(21)

A mixture solution of 2.2 g of2-[4-(tert-butoxycarbonylamino)-2,3,5,6-tetramethylanilino]acetic acid,1.67 ml of 1-benzyl-4-aminopiperidine, 10.47 g of 25% propane-phosphonicacid anhydride and 4.76 ml of triethylamine in 40 ml of methylenechloride was stirred over night at room temperature. Then, 20 ml ofsaturated sodium hydrogen carbonate solution was added to the reactionmixture, and the mixture was extracted with methylene chloride. Theextract was washed with brine, dried and concentrated under reducedpressure to give a residue. The obtained residue was purified by silicagel column chromatography (methylene chloride:methanol=10:1) to give2.48 g (73%) of2-(4-(tert-butoxycarbonylamino)-2,3,5,6-tetramethylanilino]-N-(1-benzyl-4-piperidinyl)acetamide.Then, a mixture of 438 mg of the compound obtained and 40 mg of20%-palladium hydroxide on carbon in 4 ml of methanol was stirred for 6hours under 5 atm of hydrogen. Then, the catalyst was filtered off aCelite (trade name) pad and the filtrate was concentrated under reducedpressure to give a residue. The obtained residue was purified byamine-coated silica gel (Fuji Silysia Chemical Ltd.; NH-DM1020) columnchromatography (methylene chloride:methanol=10:1) to give 293 mg (81%)of the above-mentioned compound (21).

Example 222-(4-Dimethylamino-2,3,5,6-tetramethylanilino)-N-methyl-N-(4-piperidinyl)acetamide(22)

The title compound (22) was obtained from2-(4-dimethylamino-2,3,5,6-tetramethylanilino)acetic acid and1-(tert-butoxycarbonyl)-4-methylaminopiperidine by the same manner asthe Example 1.

Example 232-(3-Amino-2,4,6-trimethylanilino)-N-methyl-N-(4-piperidinyl)acetamide(23)

The title compound (23) was obtained from2-[3-(tert-butoxycarbonylamino)-2,4,6-trimethylanilino]acetic acid and1-(tert-butoxycarbonyl)-4-methylaminopiperidine by the same manner asthe Example 1.

Example 242-(3-Dimethylamino-2,4,6-trimethylanilino)-N-methyl-N-(4-piperidinyl)acetamide(24)

The title compound (24) was obtained from2-(3-dimethylamino-2,4,6-trimethylanilino)acetic acid and1-(tert-butoxycarbonyl)-4-methylaminopiperidine by the same manner asthe Example 1.

Example 252-(2-Amino-4,5-dimethylanilino)-N-methyl-N-C(4-piperidinyl)acetamide(25)

The title compound (25) was obtained from2-[2-(tert-butoxycarbonylamino)-4,5-dimethylanilino]acetic acid and1-(tert-butoxycarbonyl)-4-methylaminopiperidine by the same manner asthe Example 1.

Example 262-(4-Amino-2,5-dichloroanilino)-N-methyl-N-(4-piperidinyl)acetamide (26)

The title compound (26) was obtained from2-[4-(tert-butoxycarbonylamino)-2,5-dichloroanilino]acetic acid and1-(tert-butoxycarbonyl)-4-methylaminopiperidine by the same manner asthe Example 1.

Example 272-(4-Nitro-2,6-dichloroanilino)-N-methyl-N-(4-piperidinyl)acetamide (27)

The title compound (27) was obtained from2-(4-nitro-2,6-dichloroanilino)acetic acid and1-(tert-butoxycarbonyl)-4-methylaminopiperidine by the same manner asthe Example 1.

Example 282-(4-Amino-2,3,5-trimethylphenoxy)-N-methyl-N-(1-phenethyl-4-piperidinyl)acetamide(28)

200 mg of phenethyl bromide was added to a mixture solution of 350 mg ofthe Compound (1) obtained in the Example 1 and 172 mg of triethylaminein 5 ml of acetonitrile, and the mixture was stirred for 5 hours at 60°C. Then, 5 ml of saturated ammonium chloride solution was added to thereaction mixture and the mixture was extracted with ethyl acetate. Theextract was washed with brine, dried and concentrated under reducedpressure to give a residue. The obtained residue was purified byamine-coated silica gel (Fuji Silysia Chemical Ltd.; NH-DM1020) columnchromatography (methylene chloride:methanol=20:1) to give 390 mg (83%)of the above-mentioned compound (28).

Example 292-(4-Amino-2,3,5-trimethylphenoxy)-N-[1-(2-anilino-2-oxyethyl)-4-piperidinyl]-N-methylacetamide(29)

The title compound (29) was obtained by the same manner as the Example28 from the Compound (1) obtained in the Example 1 andN-phenyl-2-bromoacetamide.

Example 302-(4-Amino-2,3,5-trimethylphenoxy)-N-[1-(2-anilino-2-oxyethyl)-4-piperidinyl]-N-methylpropamide(30)

The title compound (30) was obtained by the same manner as the Example28 from the Compound (2) obtained in the Example 2 andN-phenyl-2-bromoacetamide.

Example 312-(4-Amino-2,3,5-trimethylphenoxy)-N-methyl-N-(1-phenthyl-4-piperidinyl)propamide(31)

The title compound (31) was obtained by the same manner as the Example28 from the Compound (2) obtained in the Example 2 and phenethylbromide.

Example 322-(4-Amino-2,3,5-trimethylphenoxy)-N-[1-(2-(4-amino-2,3,5,6-tetramethyl)anilino-2-oxyethyl)-4-piperidinyl]-N-methyl-propamide(32)

The title compound (32) was obtained by the same manner as the Example28 from the Compound (2) obtained in the Example 2 andN-(4-amino-2,3,5,6-tetramethyl)phenyl-2-bromoacetamide.

Example 332-(4-Amino-2,3,5-trimethylphenoxy)-N-methyl-N-[1-(2-quinolylmethyl)-4-piperidinyl]propamide(33)

The title compound (33) was obtained by the same manner as the Example28 from the Compound (2) obtained in the Example 2 and 2-quinolylmethylbromide.

Example 342-(4-Amino-2,3,5-trimethylphenoxy)-N-[1-(2-(4-amino-2,3,5,6-tetramethyl)anilino-2-oxyethyl)-4-piperidinyl]-N-methyl-acetamide(34)

The title compound (34) was obtained by the same manner as the Example28 from the Compound (1) obtained in the Example 1 andN-(4-amino-2,3,5,6-tetramethyl)phenyl-2-bromoacetamide.

Example 352-(4-Amino-2,3,5-trimethylphenoxy)-N-[1-(2-benzimidazolylmethyl)-4-piperidinyl]-N-methylpropamide(35)

The title compound (35) was obtained by the same manner as the Example28 from the Compound (2) obtained in the Example 2 and2-benzimidazolylmethyl bromide.

Example 362-(2-Amino-4,6-dimethylphenoxy)-N-methyl-N-[1-(2-pyridylmethyl)-4-piperidinyl]acetamide(36)

The title compound (36) was obtained by the same manner as the Example28 from the Compound (4) obtained in the Example 4 and 2-pyridylmethylbromide.

Example 372-(4-Amino-2,3,6-trimethylphenoxy)-N-methyl-N-[1-(2-phenethyl)-4-piperidinyl]acetamide(37)

The title compound (37) was obtained by the same manner as the Example28 from the Compound (5) obtained in the Example 5 and phenethylbromide.

Example 382-(4-Amino-2,3,5-trimethylphenoxy)-2-methyl-N-methyl-N-[1-(2-phenethyl)-4-piperidinyl]propamide(38)

The title compound (38) was obtained by the same manner as the Example28 from the Compound (3) obtained in the Example 3 and phenethylbromide.

Example 392-(4-Amino-2,3,6-trimethylphenoxy)-N-[1-(2-(4-amino-2,5-dichloroanilino)-2-oxyethyl)-4-piperidinyl]-N-methylacetamide(39)

The title compound (39) was obtained by the same manner as the Example28 from the Compound (5) obtained in the Example 5 andN-(4-amino-2,5-dichloro)phenyl-2-bromoacetamide.

Example 402-(4-Amino-2,3,5,6-tetramethylanilino)-N-methyl-N-[1-(2-phenethyl)-4-piperidinyl]acetamide(40)

The title compound (40) was obtained by the same manner as the Example28 from the Compound (10) obtained in the Example 10 and phenethylbromide.

Example 412-(4-Amino-2,3,5,6-tetramethylanilino)-N-[1-(2-anilino-2-oxyethyl)-4-piperidinyl]-N-methylacetamide(41)

The title compound (41) was obtained by the same manner as the Example28 from the Compound (10) obtained in the Example 10 andN-phenyl-2-bromoacetamide.

Example 422-(4-Amino-2,3,5-trimethylphenoxy)-2-methyl-N-[1-(2-anilino-2-oxyethyl)-4-piperidinyl]-N-methylpropamide(42)

The title compound (42) was obtained by the same manner as the Example28 from the Compound (3) obtained in the Example 3 andN-phenyl-2-bromoacetamide.

Example 432-(4-Amino-2,3,5-trimethylphenoxy)-N-[1-(2-(2,5-dimethyl-4-hydroxy)anilino-2-oxyethyl)-4-piperidinyl]-N-methyl-acetamide(43)

The title compound (43) was obtained by the same manner as the Example28 from the Compound (1) obtained in the Example 1 andN-(2,5-dimethyl-4-hydroxy)phenyl-2-bromoacetamide.

Example 442-(4-Amino-2,3,5-trimethylphenoxy)-N-methyl-N-[1-(2-quinolylmethyl)-4-piperidinyl]acetamide(44)

The title compound (44) was obtained by the same manner as the Example28 from the Compound (1) obtained in the Example 1 and2-chloromethylquinoline.

Example 452-(4-Amino-2,3,5-trimethylphenoxy)-N-[1-(2-(3-chloro-2-methyl)anilino-2-oxyethyl)-4-piperidinyl]-N-methylacetamide

The title compound (45) was obtained by the same manner as the Example28 from the Compound (1) obtained in the Example 1 andN-(3-chloro-2-methyl)phenyl-2-bromoacetamide.

Example 462-(4-Amino-2,3,5-trimethylphenoxy)-N-[1-(2-(2-tert-butyl)anilino-2-oxyethyl)-4-piperidinyl]-N-methylacetamide(46)

The title compound (46) was obtained by the same manner as the Example28 from the Compound (1) obtained in the Example 1 andN-(2-tert-butyl)phenyl-2-bromoacetamide.

Example 472-(4-Amino-2,3,5-trimethylphenoxy)-N-[1-(2-(2,6-dimethyl)anilino-2-oxyethyl)-4-piperidinyl]-N-methylacetamide

The title compound (47) was obtained by the same manner as the Example28 from the Compound (1) obtained in the Example 1 andN-(2,6-dimethyl)phenyl-2-bromoacetamide.

Example 482-(4-Amino-2,3,5-trimethylphenoxy)-2-methyl-N-[1-(2-(3-chloro-2-methyl)anilino-2-oxyethyl)-4-piperidinyl]-N-methylpropamide(48)

The title compound (48) was obtained by the same manner as the Example28 from the Compound (3) obtained in the Example 3 andN-(3-chloro-2-methyl)phenyl-2-bromoacetamide.

Example 492-(4-Amino-2,3,5-trimethylphenoxy)-2-methyl-N-[1-(2-tert-butylanilino-2-oxyethyl)-4-piperidinyl]-N-methylpropamide(49)

The title compound (49) was obtained by the same manner as the Example28 from the Compound (3) obtained in the Example 3 andN-(2-tert-butylmethyl)phenyl-2-bromoacetamide.

Example 502-(4-Amino-2,3,5-trimethylphenoxy)-2-methyl-N-[1-(2-(2,6-dimethyl)anilino-2-oxyethyl)-4-piperidinyl]-N-methyl-propamide(50)

The title compound (50) was obtained by the same manner as the Example28 from the Compound (3) obtained in the Example 3 andN-(2,6-dimethyl)phenyl-2-bromoacetamide.

Example 512-(5-Amino-4-chloro-2-methoxyphenoxy)-N-[1-(2-anilino-2-oxyethyl)-4-piperidinyl]-N-ethylacetamide(51)

The title compound (51) was obtained by the same manner as the Example28 from the Compound (8) obtained in the Example 8 andN-phenyl-2-bromoacetamide.

Example 522-(5-Amino-4-chloro-2-methoxyphenoxy)-N-ethyl-N-[1-(2-(2,4,6-trimethyl)anilino-2-oxyethyl)-4-piperidinyl]acetamide(52)

The title compound (52) was obtained by the same manner as the Example28 from the Compound (8) obtained in the Example 8 andN-(2,4,6-trimethyl)phenyl-2-bromoacetamide.

Example 532-(4-Amino-2,3,5-trimethylphenoxy)-N-methyl-N-[1-(3-phenyl-2-(E)-propenyl)-4-piperidinyl]acetamide(53)

The title compound (53) was obtained by the same manner as the Example28 from the Compound (1) obtained in the Example 1 and cinnamyl bromide.

Example 542-(4-Amino-2,3,5-trimethylphenoxy)-N-methyl-N-[1-(1-phenyl-1-cyclopropane)methyl-4-piperidinyl]acetamide(54)

The title compound (54) was obtained by the same manner as the Example28 from the Compound (1) obtained in the Example 1 and1-phenyl-1-cyclopropylmethyl bromide.

Example 552-(4-Amino-2,3,5-trimethylphenoxy)-N-methyl-N-[1-(2-(1-phenylcyclopropyl)amino-2-oxyethyl-4-piperidinylacetamide (55)

The title compound (55) was obtained by the same manner as the Example28 from the Compound (1) obtained in the Example 1 andN-(1-phenyl)cyclopropyl-2-bromoacetamide.

Example 562-(4-Amino-2,3,5-trimethylphenoxy)-N-methyl-N-[1-(2-phenyl-2-oxyethyl)-4-piperidinyl]acetamide(56)

The title compound (56) was obtained by the same manner as the Example28 from the Compound (1) obtained in the Example 1 and phenacyl bromide.

Example 572-(5-Amino-2-methoxyphenoxy)-N-ethyl-N-[1-(2-(2,4,6-trimethyl)anilino-2-oxyethyl-4-piperidinyl]acetamide (57)

The title compound (57) was obtained by the same manner as the Example28 from the Compound (7) obtained in the Example 7 andN-(2,4,6-trimethyl)phenyl-2-bromoacetamide.

Example 582-(5-Amino-2-methoxyphenoxy)-N-methyl-N-[1-(2-(2,4,6-trimethyl)anilino-2-oxyethyl)-4-piperidinyl]acetamide(58)

The title compound (58) was obtained by the same manner as the Example28 from the Compound (6) obtained in the Example 6 andN-(2,4,6-trimethyl)phenyl-2-bromoacetamide.

Example 592-(5-Amino-2-methoxyphenoxy)-N-[1-(2-anilino-2-oxyethyl)-4-piperidinyl]-N-methylacetamide(59)

The title compound (59) was obtained by the same manner as the Example28 from the Compound (6) obtained in the Example 6 andN-phenyl-2-bromoacetamide.

Example 602-(4-Amino-2,3,5-trimethylphenoxy)-N-[1-(2-(2-tert-butylanilino)-2-oxyethyl)-4-piperidinyl]-N-methylpropamide(60)

The title compound (60) was obtained by the same manner as the Example28 from the Compound (2) obtained in the Example 2 andN-(2-tert-butyl)phenyl-2-bromoacetamide.

Example 612-(4-Amino-2,3,5-trimethylphenoxy)-N-[1-(2-(2,6-dimethylanilino)-2-oxyethyl)-4-piperidinyl]-N-methylpropamide(61)

The title compound (61) was obtained by the same manner as the Example28 from the Compound (2) obtained in the Example 2 andN-(2,6-dimethyl)phenyl-2-bromoacetamide.

Example 622-(4-Amino-2,3,5-trimethylphenoxy)-N-methyl-N-[1-(3-phenyl-2-(E)-propenyl)-4-piperidinyl]propamide(62)

The title compound (62) was obtained by the same manner as the Example28 from the Compound (2) obtained in the Example 2 and cinnamyl bromide.

Example 632-(4-Amino-2,3,5-trimethylphenoxy)-N-methyl-N-[1-(trans-2-phenyl-1-cyclopropylmethyl)-4-piperidinyl]propamide(63)

The title compound (63) was obtained by the same manner as the Example28 from the Compound (2) obtained in the Example 2 andtrans-2-phenyl-1-cyclopropylmethyl bromide.

Example 642-(4-Amino-2,3,5-trimethylphenoxy)-N-methyl-N-[1-(2-(1-phenylcyclopropyl)amino-2-oxyethyl)-4-piperidinyl]propamide(64)

The title compound (64) was obtained by the same manner as the Example28 from the Compound (2) obtained in the Example 2 andN-(1-phenyl)cyclopropyl-2-bromoacetamide.

Example 652-(4-Amino-2,3,5-trimethylphenoxy)-N-methyl-N-[1-(2-hydroxy-3-phenoxy)propyl-4-piperidinyl]acetamide(65)

A mixture solution of 330 mg of Compound (1) obtained in the Example 1and 162 mg of glycidyl phenyl ether in 8 ml of iso-propanol was stirredfor 4 hours at 80° C. Then, the reaction mixture was concentrated underreduced pressure, and the resultant residue was purified by amine-coatedsilica gel (Fuji Silysia Chemical Ltd.; NH-DM1020) column chromatography(chloroform:methanol=30:1) to give 266 mg (54%) of the title compound(65).

Example 662-(4-Amino-2,3,5-trimethylphenoxy)-N-methyl-N-[1-(2-trans-2-phenyl-1-cyclopropyl)amino-2-oxyethyl)-4-piperidinyl]acetamide(66)

The title compound (66) was obtained by the same manner as the Example28 from the Compound (1) obtained-in the Example 1 and2-bromo-N-(trans-2-phenylcyclopropyl)acetamide.

Example 672-(4-Amino-2,3,5-trimethylphenoxy)-2-methyl-N-methyl-N-{1-(3-phenyl-2-(E)-propenyl)-4-piperidinyl]propamide(67)

The title compound (67) was obtained by the same manner as the Example28 from the Compound (3) obtained in the Example 3 and cinnamyl bromide.

Example 682-(4-Amino-2,3,5-trimethylphenoxy)-2-methyl-N-methyl-N-[1-(1-phenyl-1-cyclopropane)methyl-4-piperidinyl]propamide (68)

The title compound (68) was obtained by the same manner as the Example28 from the Compound (3) obtained in the Example 3 and1-phenyl-1-cyclopropylmethyl bromide.

Example 692-(4-Amino-2,3,5-trimethylphenoxy)-2-methyl-N-methyl-N-[1-(2-(1-phenylcyclopropyl)amino-2-oxyethyl)-4-piperidinyl]propamide(69)

The title compound (69) was obtained by the same manner as the Example28 from the Compound (3) obtained in the Example 3 andN-(1-phenyl)cyclopropyl-2-bromoacetamide.

Example 702-(4-Amino-2,3,5,6-tetramethylanilino)-N-methyl-N-[1-(1-phenyl-1-cyclopropane)methyl-4-piperidinyl]acetamide(70)

The title compound (70) was obtained by the same manner as the Example.28 from the Compound (10) obtained in the Example 10 and1-phenyl-1-cyclopropylmethyl bromide.

Example 712-(4-Amino-2,3,5-trimethylphenoxy)-N-[1-(2-anilino-2-oxyethyl)-4-piperidinyl]-N-ethylacetamide(71)

The title compound (71) was obtained by the same manner as the Example28 from the Compound. (14) obtained in the Example 14 andN-phenyl-2-bromoacetamide.

Example 722-(4-Amino-2-chloro-3,5,6-trimethylphenoxy)-N-methyl-N-[1-(2-(1-phenylcyclopropyl)amino-2-oxyethyl)-4-piperidinyl]-acetamide(72)

The title compound (72) was obtained by the same manner as the Example28 from the Compound (16) obtained in the Example 16 andN-(1-phenyl)cyclopropyl-2-bromoacetamide.

Example 732-(4-Amino-2-chloro-3,5,6-trimethylphenoxy)-N-[1-(2-anilino-2-oxyethyl)-4-piperidinyl]-N-ethylacetamide(73)

The title compound (73) was obtained by the same manner as the Example28 from the Compound (9) obtained in the Example 9 andN-phenyl-2-bromoacetamide.

Example 742-(4-Amino-2,3,5-trimethylphenoxy)-N-ethyl-N-[1-(3-phenyl-2-(E)-propenyl)-4-piperidinyl]acetamide(74)

The title compound (74) was obtained by the same manner as the Example28 from the Compound (14) obtained in the Example 14 and cinnamylbromide.

Example 752-(4-Amino-2,3,5-trimethylphenoxy)-N-[1-(2-anilino-2-oxyethyl)-4-piperidinyl]-N-ethylpropamide(75)

The title compound (75) was obtained by the same manner as the Example28 from the Compound (15) obtained in the Example 15 andN-phenyl-2-bromoacetamide.

Example 762-(4-Amino-2,3,5,6-tetramethylanilino)-N-ethyl-N-[1-(2-phenethyl)-4-piperidinyl]acetamide(76)

The title compound (76) was obtained by the same manner as the Example28 from the Compound (18) obtained in the Example 18 and phenethylbromide.

Example 772-(4-Amino-2,3,5-trimethylphenoxy)-N-ethyl-N-[1-(3-phenyl-2-(E)-propenyl)-4-piperidinyl]propamide(77)

The title compound (77) was obtained by the same manner as the Example28 from the Compound (15) obtained in the Example 15 and cinnamylbromide.

Example 782-(4-Amino-2,3,5,6-tetramethylanilino)-N-ethyl-N-[1-(3-phenyl-2-(E)-propenyl)-4-piperidinyl]acetamide(78)

The title compound (78) was obtained by the same manner as the Example28 from the Compound (18) obtained in the Example 18 and cinnamylbromide.

Example 792-(4-Amino-2,3,5-trimethylphenoxy)-2-methyl-N-[1-(2-(4-amino-2,5-dichloro)anilino-2-oxyethyl)-4-piperidinyl]-N-methylpropamide(79)

The title compound (79) was obtained by the same manner as the Example28 from the Compound (3) obtained in the Example 3 andN-(4-amino-2,5-dichloro)phenyl-2-bromoacetamide.

Example 802-(4-Amino-2,3,5-trimethylphenoxy)-2-methyl-N-[1-(3-phenyl-2-(E)-propenyl)-4-piperidinyl]propamide(80)

The title compound (80) was obtained by the same manner as the Example28 from the Compound (13) obtained in the Example 13 and cinnamylbromide.

Example 812-(4-Amino-2,3,5-trimethylphenoxy)-2-methyl-N-[1-(1-phenyl-1-cyclopropane)methyl-4-piperidinyl]propamide(81)

The title compound (81) was obtained by the same manner as the Example28 from the Compound (13) obtained in the Example 13 and1-phenyl-1-cyclopropylmethyl bromide.

Example 822-(4-Amino-2,3,5-trimethylphenoxy)-2-methyl-N-[1-(2-anilino-2-oxyethyl)-4-piperidinyl]propamide(82)

The title compound (82) was obtained by the same manner as the Example28 from the Compound (13) obtained in the Example 13 andN-phenyl-2-bromoacetamide.

Example 832-(4-Amino-2,3,5-trimethylphenoxy)-N-[1-(2-anilino-2-oxyethyl)-4-piperidinyl]propamide(83)

The title compound (83) was obtained by the same manner as the Example28 from the Compound (12) obtained in the Example 12 andN-phenyl-2-bromoacetamide.

Example 842-(4-Amino-2,3,5-trimethylphenoxy)-N-[1-(3-phenyl-2-(E)-propenyl)-4-piperidinyl]propamide(84)

The title compound (84) was obtained by the same manner as the Example28 from the Compound (12) obtained in the Example 12 and cinnamylbromide.

Example 852-(4-Amino-2,3,5-trimethylphenoxy)-N-[1-(2-anilino-2-oxyethyl)-4-piperidinyl]acetamide(85)

The title compound (85) was obtained by the same manner as the Example28 from the Compound (11) obtained in the Example 11 andN-phenyl-2-bromoacetamide.

Example 862-(4-Amino-2,3,5-trimethylphenoxy)-N-[1-(3-phenyl-2-(E)-propenyl)-4-piperidinyl]acetamide(86)

The title compound (86) was obtained by the same manner as the Example28 from the Compound (11) obtained in the Example 11 and cinnamylbromide.

Example 872-(4-Amino-2,3,5-trimethylphenoxy)-N-ethyl-N-[1-(1-phenyl-1-cyclopropane)methyl-4-piperidinyl]propamide(87)

The title compound (87) was obtained by the same manner as the Example28 from the Compound (15) obtained in the Example 15 and1-phenyl-1-cyclopropylmethyl bromide.

Example 882-(4-Amino-2,3,5,6-tetramethylanilino)-N-ethyl-N-[1-(1-phenyl-1-cyclopropane)methyl-4-piperidinyl]acetamide(88)

The title compound (88) was obtained by the same manner as the Example28 from the Compound (18) obtained in the Example 18 and1-phenyl-1-cyclopropylmethyl bromide.

Example 892-(4-Amino-2,3,5-trimethylphenoxy)-N-[1-(2-(4-amino-2,5-dichloro)anilino-2-oxyethyl)-4-piperidinyl]-N-methylacetamide(89)

The title compound (89) was obtained by the same manner as the Example28 from the Compound (1) obtained in the Example 1 andN-(4-amino-2,5-dichloro)phenyl-2-bromoacetamide.

Example 902-(4-Amino-2,3,5-trimethylphenoxy)-N-methyl-N-[1-(1-phenyl-1-cyclopropane)methyl-4-piperidinyl]propamide(90)

The title compound (90) was obtained by the same manner as the Example28 from the Compound (2) obtained in the Example 2 and1-phenyl-1-cyclopropylmethyl bromide.

Example 912-(4-Amino-2-chloro-3,5,6-trimethylphenoxy)-N-[1-(2-anilino-2-oxyethyl)-4-piperidinyl]acetamide(91)

The title compound (91) was obtained by the same manner as the Example28 from the Compound (17) obtained in the Example 17 andN-phenyl-2-bromoacetamide.

Example 922-(4-Amino-2-chloro-3,5,6-trimethylphenoxy)-N-[1-(2-(4-amino-2,5-dichloro)anilino-2-oxyethyl)-4-piperidinyl]-N-methylacetamide(92)

The title compound (92) was obtained by the same manner as the Example28 from the Compound (16) obtained in the Example 16 andN-(4-amino-2,5-dichloro)phenyl-2-bromoacetamide.

Example 932-(4-Amino-2-chloro-3,5,6-trimethylphenoxy)-N-[1-(2-(2,5-dimethyl-4-hydroxy)anilino-2-oxyethyl)-4-piperidinyl]-N-ethylacetamide(93)

The title compound (93) was obtained by the same manner as the Example28 from the Compound (9) obtained in the Example 9 andN-(2,5-dimethyl-4-hydroxy)phenyl-2-bromoacetamide.

Example 942-(4-Amino-2,3,5,6-tetramethylanilino)-N-ethyl-N-[1-(trans-2-phenyl-1-cyclopropylmethyl)-4-piperidinyl]acetamide(94)

The title compound (94) was obtained by the same manner as the Example28 from the Compound (18) obtained in the Example 18 andtrans-2-phenyl-1-cyclopropylmethyl bromide.

Example 952-(4-Amino-2,3,5-trimethylphenoxy)-N-[1-(trans-2-phenyl-1-cyclopropylmethyl)-4-piperidinyl]acetamide(95)

The title compound (95) was obtained by the same manner as the Example28 from the Compound (11) obtained in the Example 11 andtrans-2-phenyl-1-cyclopropylmethyl bromide.

Example 962-(4-Amino-2,3,5-trimethylphenoxy)-N-[1-(1-phenyl-1-cyclopropane)methyl-4-piperidinyl]acetamide(96)

The title compound (96).was obtained by the same manner as the Example28 from the Compound (11) obtained in the Example 11 and1-phenyl-1-cyclopropylmethyl bromide.

Example 972-(4-Amino-2,3,5-trimethylphenoxy)-N-(1-(2-phenethyl)-4-piperidinyl)acetamide(97)

The title compound (97) was obtained by the same manner as the Example28 from the Compound (11) obtained in the Example 11 and phenethylbromide.

Example 982-(4-Amino-2,3-5-trimethylphenoxy)-2-methyl-N-[1-(2-(2,6-dimethylanilino)-2-oxyethyl)-4-piperidinyl]propamide(98)

The title compound (98) was obtained by the same manner as the Example28 from the Compound (13) obtained in the Example 13 andN-(2,6-dimethylphenyl)-2-bromoacetamide.

Example 992-(4-Amino-2,3,5-trimethylphenoxy)-2-methyl-N-[1-(trans-2-phenyl-1-cyclopropylmethyl)-4-piperidinyl]propamide(99)

The title compound (99) was obtained by the same manner as the Example28 from the Compound (13) obtained in the Example 13 andtrans-2-phenyl-1-cyclopropylmethyl bromide.

Example 1002-(4-Amino-2,3,5-trimethylphenoxy)-2-methyl-N-[1-(2-(2-tert-butylanilino)-2-oxyethyl)-4-piperidinyl]propamide(100)

The title compound (100) was obtained by the same manner as the Example28 from the Compound (13) obtained in the Example 13 andN-(2-tert-butylphenyl)-2-bromoacetamide.

Example 1012-(4-Amino-2,3,5-trimethylphenoxy)-N-[1-(1-phenyl-1-cyclopropane)methyl-4-piperidinyl]propamide(101)

The title compound (101) was obtained by the same manner as the Example28 from the Compound (12) obtained in the Example 12 and1-phenyl-1-cyclopropylmethyl bromide.

Example 1022-(4-Amino-2,3,5-trimethylphenoxy)-N-[1-(2-(1-phenylcyclopropyl)amino-2-oxyethyl)-4-piperidinyl]propamide(102)

The title compound (102) was obtained by the same manner as the Example28 from the Compound (12) obtained in the Example 12 andN-(1-phenyl)cyclopropyl-2-bromoacetamide.

Example 1032-(4-Amino-2,3,5-trimethylphenoxy)-N-methyl-N-[1-(2-hydroxy-3-phenoxy)propyl-4-piperidinyl]propamide(103)

The title compound (103) was obtained by the same manner as the Example65 from the Compound (2) obtained in the Example 2.

Example 1042-(4-Amino-2,3,5-trimethylphenoxy)-N-[1-(2-(1-phenylcyclopropyl)amino-2-oxyethyl)-4-piperidinyl]acetamide(104)

The title compound (104) was obtained by the same manner as the Example28 from the Compound (11) obtained in the Example 11 andN-(1-phenyl)cyclopropyl-2-bromoacetamide.

Example 1052-(4-Amino-2,3,5-trimethylphenoxy)-N-methyl-N-[1-(2-(N-methylanilino)-2-oxyethyl)-4-piperidinyl]acetamide(105)

The title compound (105) was obtained by the same manner as the Example28 from the Compound (1) obtained in the Example 1 andN-methyl-N-phenyl-2-bromoacetamide.

Example 1062-(4-Amino-2,3,5-trimethylphenoxy)-N-[1-(trans-2-phenyl-1-cyclopropylmethyl)-4-piperidinyl]propamide(106)

The title compound (106) was obtained by the same manner as the Example28 from the Compound (12) obtained in the Example 12 andtrans-2-phenyl-1-cyclopropylmethyl bromide.

Example 1072-(4-Amino-2,3,5-trimethylphenoxy)-2-methyl-N-[1-(2-(2,5-dimethyl-4-hydroxy)anilino-2-oxyethyl]-4-piperidinyl]-N-methylpropamide(107)

The title compound (107) was obtained by the same manner as the Example28 from the Compound (3) obtained in the Example 3 andN-(2,5-dimethyl-4-hydroxy)phenyl-2-bromoacetamide.

Example 1082-(4-Amino-2,3,5-trimethylphenoxy-N-[1-(2-(N-methylanilino)-2-oxyethyl)-4-piperidinyl]acetamide(108)

The title compound (108) was obtained by the same manner as the Example28 from the Compound (11) obtained in the Example 11 andN-methyl-N-phenyl-2-bromoacetamide.

Example 1093{4-[[2-(4-Amino-2,3,5,6-tetramethylanilino)-acetyl](methyl)amino]-1-piperidino}-2-phenylpropionicacid (109)

A mixture solution of 144 mg of{4-[(tert-butoxycarbonyl)amino]-2,3,5,6-tetramethylanilino}acetic acid,156 mg of ethyl 3-[4-(methylamino)-1-piperidino]-2-phenyl propionate,860 mg of 25% propanephosphonic acid anhydride and 436 μl oftriethylamine in 2 ml of methylene chloride was stirred over night atroom temperature. Then, saturated sodium hydrogen carbonate solution wasadded to the reaction mixture, and the mixture was extracted withmethylene chloride. The extract was washed with brine, dried, filtrated,and concentrated under reduced pressure to give a residue. The obtainedresidue was purified by silica gel column chromatography (methylenechloride:methanol=10:1) to give 180 mg (67%) of ethyl3-{4-[((4-[(tert-butoxycarbonyl)amino]-2,3,5,6-tetramethylanilino}-acetyl)(methyl)amino]-1-piperidino}-2-phenylpropionate. Then, 178 mg of the obtained ethyl propionate was dissolvedin 3 ml of 1,4-dioxane and 3 ml of 0.3N-litium hydroxide solution wasadded to this solution, then the mixture solution was stirred for 4hours at room temperature. Then, the reaction mixture was acidified (pH4) with conc. HCl solution and the mixture was extracted with ethylacetate. The extract was washed with brine, dried, filtrated andconcentrated under reduced pressure to give a residue. Then, a mixturesolution of the obtained residue in methylene chloride andtrifluoroacetic acid (4:1) was stirred for 1 hour at room temperature.Then, the solvent was removed and the residue was dissolved in water andthen treated with 4N—HCl solution to give 130 mg (81%) of theabove-mentioned compound (109).

Example 1102-(4-Amino-2,3,5,6-tetramethylanilino)-N-(1-benzyl-4-piperidinyl]-N-methylacetamide(110)

The title compound (110) was obtained by the same manner as the Example28 from the Compound (10) obtained in the Example 10 and benzyl bromide.

Example 1112-(4-Amino-2,3,5,6-tetramethylanilino)-N-methyl-[1-(2-phenyl-2-oxyethyl)-4-piperidinyl]acetamide(111)

The title compound (111) was obtained by the same manner as the Example28 from the Compound (10) obtained in the Example 10 and phenacylbromide.

Example 1122-(4-Amino-2,3,5,6-tetramethylanilino)-N-[1-(2-hydroxy-2-phenylethyl)-4-piperidinyl]-N-methylacetamide(112)

To a solution of the Compound (111) obtained in the Example 111 inmethanol was added 1.0 equivalent of sodium borohydride at 0° C., andthe mixture was stirred for 2.5 hours at room temperature. Then, thesolvent was removed and the obtained residue was purified byamine-coated silica gel (Fuji Silysia Chemical Ltd.; NH-DM1020) columnchromatography (ethyl acetate hexane:methanol=10:10:1) to give theabove-mentioned compound (112) in 75% yield.

Example 1132-(4-Amino-2,3,5,6-tetramethylanilino)-N-[1-(cyclopropylmethyl-4-piperidinyl]-N-methylacetamide(113)

The title compound (113) was obtained by the same manner as the Example28 from the Compound (10) obtained in the Example 10 andcyclopropylmethyl bromide.

Example 1142-(4-Amino-2,3,5,6-tetramethylanilino)-N-methyl-N-[1-(4-pyridylmethyl)-4-piperidinyl]acetamide(114)

The title compound (114) was obtained by the same manner as the Example28 from the Compound (10) obtained in the Example 10 and 4-picolylchloride.

Example 115 4-({4-[[(4-Amino-2,3,5,6-tetramethylanilino)-acetyl](methylamino]-1-piperidino}methyl)benzoic acid (115)

A mixture solution of the compound obtained from the Compound (10) inthe Example 10 and tert-butyl 4-(bromomethyl)benzoate by the same manneras the Example 28 in 6N—HCl solution was refluxed for 2 hours. Then, thesolvent was removed to give the title compound (115).

Example 116 4-({4-[[(4-Amino-2,3,5,6-tetramethylanilino)-acetyl](methylamino]-1-piperidino}methyl)benzamide (116)

The title compound (116) was obtained by the same manner as the Example28 from the Compound (10) obtained in the Example 10 and4-bromomethylbenzamide.

Example 1172-(4-Amino-2,3,5,6-tetramethylanilino)-N-[1-(2-hydroxyethyl)-4-piperidinyl]-N-methylacetamide(117)

The title compound (117) was obtained by the same manner as the Example28 from the Compound (10) obtained in the Example 10 and 2-bromoethanol.

Example 1183-{4-[[(4-Amino-2,3,5,6-tetramethylanilino)-acetyl](methyl)amino]-1-piperidino}propionicacid (118)

The title compound (118) was obtained by the same manner as the Example115 from the Compound (10) obtained in the Example 10 and tert-butyl3-bromopropionate.

Example 1192-(4-Amino-2,3,5,6-tetramethylanilino)-N-methyl-N-{1-[2-(4-morpholinyl)ethyl]-4-piperidinyl}acetamide(119)

The title compound (119) was obtained by the same manner as the Example28 from the Compound (10) obtained in the Example 10 andN-(2-bromoethyl)morpholine hydrochloride.

Example 1202-(4-Amino-2,3,5,6-tetramethyl-N-methylanilino)-N-methyl-N-[1-(2-phenethyl)-4-piperidinyl]acetamide(120)

The title compound (120) was obtained by the same manner as the Example28 from the Compound (19) obtained in the Example 19 and phenethylbromide.

Example 1212-(4-Amino-2,3,5,6-tetramethylanilino)-N-[1-(cyclopropylmethyl)-4-piperidinyl]-N-methylpropamide(121)

The title compound (121) was obtained by the same manner as the Example28 from the Compound (20) obtained in the Example 20 andcyclopropylmethy bromide.

Example 1222-(4-Amino-2,3,5,6-tetramethylanilino)-N-methyl-N-[1-(2-phenethyl)-4-piperidinyl]propamide(122)

The title compound (122) was obtained by the same manner as the Example28 from the Compound (20) obtained in the Example 20 and phenethylbromide.

Example 1232-(4-Amino-2,3,5,6-tetramethylanilino)-N-[1-(2-phenethyl)-4-piperidinyl]acetamide(123)

A mixture solution of the compound obtained from the Compound (21) inthe Example 21 and phenethyl bromide by the same manner as the Example28 in methylene chloride and trifluoroacetic acid (4:1) was stirred for1 hour at 0° C. Then, the solvent was removed to give a residue, and theobtained residue was purified by amine-coated silica gel (Fuji SilysiaChemical Ltd.; NH-DM1020) column chromatography (methylenechloride:methanol=10:1) to give the above-mentioned compound (123) in60% yield.

Example 1242-(4-Dimethylamino-2,3,5,6-tetramethylanilino)-N-methyl-N-[1-(2-phenethyl)-4-piperidinyl]acetamide(124)

The title compound (124) was obtained by the same manner as the Example28 from the Compound (22) obtained in the Example 22 and phenethylbromide.

Example 1252-(3-Amino-2,4,6-trimethylanilino)-N-methyl-N-[1-(3-phenyl-2-(E)-propenyl)-4-piperidinyl]acetamide(125)

The title compound (125) was obtained by the same manner as the Example28 from the Compound (23) obtained in the Example 23 and cinnamylbromide.

Example 1262-(3-Amino-2,4,6-tirmethylanilino)-N-[1-(2-hydroxy-3-phenoxy)propyl-4-piperidinyl]-N-methylacetamide(126)

The title compound (126) was obtained by the same manner as the Example65 from the Compound (23) obtained in the Example

Example 1272-(3-Amino-2,4,6-trimethylanilino)-N-methyl-N-[1-(2-phenyl-2-oxyethyl)-4-piperidinyl]acetamide(127)

The title compound (127) was obtained by the same manner as the Example28 from the Compound (23) obtained in the Example 23 and phenacylbromide.

Example 1282-(3-Amino-2,4,6-trimethylanilino)-N-(1-benzoyl-4-piperidinyl)-N-methylacetamide(128)

A mixture solution of 300 mg of the compound (23) obtained in theExample 23, 114 μl of benzoyl chloride and 206 μl of triethylamine in 5ml of methylene chloride were stirred for 2 hours at 0° C. After thereaction, the solvent was removed and the obtained residue was purifiedby amine-coated silica gel (Fuji Silysia Chemical Ltd.; NH-DM1020)column chromatography (methylene chloride:ether=1:1) to give theabove-mentioned compound (128) in 66% yield.

Example 1292-(3-Amino-2,4,6-trimethylanilino)-N-[1-(cyclopropylmethyl)-4-piperidinyl]-N-methylacetamide(129)

The title compound (129) was obtained by the same manner as the Example28 from the Compound (23) obtained in the Example 23 andcyclopropylmethyl bromide.

Example 1302-(3-Amino-2,4,6-trimethylanilino)-N-methyl-N-[1-(phenylsulfonyl)-4-piperidinyl]acetamide(130)

The title compound (130) was obtained by the same manner as the Example128 from the Compound (23) obtained in the Example 23 andbenzenesulfonyl chloride.

Example 1312-(3-Amino-2,4,6-trimethylanilino)-N-(1-benzyl-4-piperidinyl)-N-methylacetamide(131)

The title compound (131) was obtained by the same manner as the Example28 from the Compound (23) obtained in the Example 23 and benzyl bromide.

Example 1322-(3-Amino-2,4,6-trimethylanilino)-N-(1-butyl-4-piperidinyl)-N-methylacetamide(132)

The title compound (132) was obtained by the same manner as the Example28 from the Compound (23) obtained in the Example 23 and bromobutane.

Example 1332-(3-Amino-2,4,6-trimethylanilino)-N-methyl-N-[1-(2-naphthyl)methyl-4-piperidinyl]acetamide(133)

The title compound (133) was obtained by the same manner as the Example28 from the Compound (23) obtained in the Example 23 and2-(bromomethyl)naphthalene.

Example 1342-(3-Amino-2,4,6-trimethylanilino)-N-methyl-N-[1-(3-trifluoromethylbenzoyl)-4-piperidinyl]acetamide(134)

The title compound (134) was obtained by the same manner as the Example128 from the Compound (23) obtained in the Example 23 and3-(trifluoromethyl)benzoyl chloride.

Example 135N-(1-benzoyl-4-piperidinyl)-2-(3-dimethylamino-2,4,6-trimethylanilino)-N-methylacetamide(135)

The title compound (135) was obtained by the same manner as the Example128 from the Compound (24) obtained in the Example 24 and benzoylchloride.

Example 1362-(2-Amino-4,5-dimethylanilino)-N-methyl-N-[1-(2-phenethyl)-4-piperidinyl]acetamide(136)

The title compound (136) was obtained by the same manner as the Example28 from the Compound (25) obtained in the Example 25 and phenethylbromide.

Example 1372-(2-Amino-4-5-dimethylanilino)-N-methyl-N-[1-(trans-2-phenyl-1-cyclopropylmethyl)-4-piperidinyl]acetamide(137)

The title compound (137) was obtained by the same manner as the Example28 from the Compound (25) obtained in the Example 25 andtrans-2-phenyl-1-cyclopropylmethyl bromide.

Example 1382-(4-Amino-2,5-dichloroanilino)-N-methyl-N-[1-(2-phenethyl)-4-piperidinyl]acetamide(138)

The title compound (138) was obtained by the same manner as the Example28 from the Compound (26) obtained in the Example 26 and phenethylbromide.

Example 1392-(4-Amino-2,6-dichloroanilino)-N-[1-(2-anilino-2-oxyethyl)-4-piperidinyl]-N-methylacetamide(139)

A mixture solution of the compound obtained from the compound (27) inthe Example 27 and N-phenyl-2-bromoacetamide by the same manner as theExample 28 and 5% platinum sulfided on carbon in methanol andtetrahydrofuran was stirred for 3.5 hours under 4 atm of hydrogen. Then,the catalyst was removed by Celite (trade name) filtration. The obtainedresidue was purified by amine-coated silica gel (Fuji Silysia ChemicalLtd.; NH-DM1020) column chromatography (methylenechloride:methanol=100:1) to give the above-mentioned compound (139) in90% yield.

The physiochemical data of the compounds obtained by the above-mentionedexamples are summarized in the following tables as Table I.

Properties m. p. (° C.) No. Chemical Structure (solvent) 1

colorless cryst.(HCl salt)191-193(Et₂O/EtOH) 2

oily substance 3

foamysubstance 4

foamysubstance 5

foamysubstance 6

oily substance 7

oily substance 8

oily substance 9

colorless cryst. 10

foamysubstance 11

foamysubstance 12

foamysubstance 13

foamysubstance 14

foamysubstance 15

foamysubstance 16

foamysubstance 17

colorless cryst. 18

foamysubstance 19

oilysubstance 20

oilysubstance 21

foamysubstance 22

oilysubstance 23

foamysubstance 24

foamysubstance 25

foamysubstance 26

foamysubstance 27

foamysubstance 28

colorless cyrst.(HCl salt)183-185(EtOH/Et₂O) 29

colorless cryst.(HCl salt)177-178(EtOH/Et₂O) 30

colorless cryst.(HCl salt)191-193(EtOH/Et₂O) 31

colorless cryst.(HCl salt)197-200(MeOH/Et₂O) 32

colorless cryst.(HCl salt)220-222(MeOH/Et₂O) 33

colorless cryst.(HCl salt)173-175(MeOH/Et₂O) 34

colorless cryst.(HCl salt)215-217(MeOH/Et₂O) 35

pale yellow cryst.(HCl salt)153-155(EtOH/Et₂O) 36

colorless cryst.(HCl salt)141-143(MeOH/Et₂O) 37

colorless cryst.(HCl salt)233-235(MeOH/Et₂O) 38

colorless cryst.(HCl salt)163-165(MeOH/Et₂O) 39

colorless cryst.(HCl salt)187-189(MeOH/Et₂O) 40

colorless cryst.(HCl salt)173-175(MeOH/Et₂O) 41

colorless cryst.(HCl salt)172-174(MeOH/Et₂O) 42

colorless cryst.(HCl salt)178-180(MeOH/Et₂O) 43

colorless cryst.(HCl salt)182-184(MeOH/Et₂O) 44

pale yellowcryst.(HCl salt)174-176(MeOH/Et₂O) 45

colorless cryst.(HCl salt)178-180(MeOH/Et₂O) 46

colorless cryst.(HCI salt)186-188(MeOH/Et₂O) 47

colorless cryst.(HCl salt)189-191(MeOH/Et₂O) 48

colorless cryst.(HCl salt)172-174(MeOH/Et₂O) 49

colorless cryst.(HCl salt)178-180(MeOH/Et₂O) 50

colorless cryst.(HCl salt)177-179(MeOH/Et₂O) 51

colorless cryst.(HCl salt)162-163(iso-PrOH/Et₂O) 52

colorless cryst.(HCl salt)172-173(iso-PrOH/Et₂O) 53

colorless cryst.(HCl salt)169-171(MeOH/Et₂O) 54

colorless cryst.(HCl salt)166-108(MeOH/Et₂O) 55

colorless cryst.(HCl salt)188-190(MeOH/Et₂O) 56

colorless cryst.(HCl salt)193-195(MeOH/Et₂O) 57

colorless cryst.(HCl salt)180-184(iso-PrOH/Et₂O) 58

brown cryst.(HCl salt)226-228(EtOH/MeCN) 59

colorless cryst.(HCl salt)201-203(EtOH/MeCN) 60

colorless cryst.(HCI salt)183-185(MeOH/Et₂O) 61

colorless cryst.(HCl salt)190-192(MeOH/Et₂O) 62

pale yellowcryst.(HCl salt)178-180(MeOH/Et₂O) 63

colorless cryst.(HCl salt)169-171(MeOH/Et₂O) 64

colorless cryst.(HCl salt)182-185(MeOH/Et₂O) 65

colorless cryst.(HCl salt)176-178(MeOH/Et₂O) 66

colorless cryst.(HCl salt)186-188(MeOH/Et₂O) 67

colorless cryst.(HCl salt)178-180(MeOH/Et₂O) 68

colorless cryst.(HCl salt)167-169(iso-PrOH/Et₂O) 69

colorless cryst.(HCl salt)184-186(MeOH/Et₂O) 70

colorless cryst.(HCl salt)179-181(MeOH/Et₂O) 71

colorless cryst.(HCl salt)178-180(MeOH/Et₂O) 72

colorless cryst.(HCl salt)180-184(EtOH/Et₂O) 73

colorless cryst.(HCl salt)208-210(EtOH/Et₂O) 74

colorless cryst.(HCl salt)170-172(MeOH/Et₂O) 75

colorless cryst.(HCl salt)173-174(MeOH/Et₂O) 76

colorless cryst.(HCl salt)162-164(MeOH/Et₂O) 77

pale yellowcryst.(HCl salt)177-179(MeOH/Et₂O) 78

colorless cryst.(HCl salt)185-187(MeOH/Et₂O) 79

colorless cryst.(HCl salt) 80

colorless cryst.(HCl salt) 81

pale yellowcryst.(HCl salt)205-208(MeOH/Et₂O) 82

colorless cryst.(HCl salt) 83

colorless cryst.(HCl salt)186-190(EtOH/Et₂O) 84

pale yellowcryst.(HCl salt)232-235(EtOH/Et₂O) 85

colorless cryst.(HCl salt)178-181(MeOH/Et₂O) 86

pale yellowcryst.(HCl salt)196-198(MeOH/Et₂O) 87

colorless cryst.(HCl salt)184-187(MeOH/Et₂O) 88

colorless cryst.(HCl salt)183-186(MeOH/Et₂O) 89

colorless cryst.(HCl salt)183-186(MeOH/Et₂O) 90

colorless cryst.(HCl salt)172-175(iso-PrOH/Et₂O) 91

colorless cryst.(HCl salt)221-224(MeOH/Et₂O) 92

pale browncryst.(HCl salt)216-219(EtOH/Et₂O) 93

colorless cryst.(HCl salt)193-197(MeOH/Et₂O) 94

colorless cryst.(HCl salt)178-181(MeOH/Et₂O) 95

colorless cryst.(HCl salt)178-180(MeOH/Et₂O) 96

colorless cryst.(HCl salt)175-178(MeOH/Et₂O) 97

colorless cryst.(HCl salt)208-211(MeOH/Et₂O) 98

colorless cryst.(HCl salt) 99

colorless cryst.(HCl salt) 100

colorless cryst.(HCl salt) 101

colorless cryst.(HCl salt)200-203(EtOH/Et₂O) 102

colorless cryst.(HCl salt)190-194(EtOH/Et₂O) 103

colorless cryst.(HCl salt)143-147(iso-PrOH/Et₂O) 104

colorless cryst.(HCl salt)180-183(MeOH/Et₂O) 105

colorless cryst.(HCl salt)178-180(MeOH/Et₂O) 106

colorless cryst.(HCl salt)173-176(iso-PrOH/Et₂O) 107

colorless cryst.(HCl salt) 108

colorless cryst.(HCl salt)176-178(MeOH/Et₂O) 109

foamysubstance(HCl salt) 110

whiteamorphous(HCl salt) 111

pale yellowpowder(HCl salt)218-220(EtOH/Et₂O) 112

white cryst.(HCl salt)188-190(MeOH/Et₂O) 113

whiteamorphous(HCl salt) 114

pale yellowcryst.(HCl salt)>250(MeOH/EtOH) 115

pale yellowamorphous(HCl salt) 116

pale yellowsolid(HCl salt) 117

whiteamorphous(HCl salt) 118

pale yellowamorphous(HCl salt) 119

colorless cryst.(HCl salt)>240(MeOH/Et₂O) 120

whiteamorphous(HCl salt) 121

whiteamorphous(HCl salt) 122

colorless cryst.(HCl salt)205-209(MeOH/Et₂O) 123

whiteamorphous(HCl salt) 124

whiteamorphous(HCl salt) 125

colorless cryst.(HCl salt)174-176(MeOH/Et₂O) 126

colorless cryst.(HCl salt)163-165(MeOH/Et₂O) 127

colorless cryst.(HCl salt)182-183(MeOH/Et₂O) 128

colorless cryst.(HCl salt)166-168(MeOH/Et₂O) 129

colorless cryst.(HCl salt)173-175(MeOH/Et₂O) 130

whiteamorphous(HCl salt) 131

colorless cryst.(HCl salt)176-178(MeOH/Et₂O) 132

colorless cryst.(HCl salt)172-174(MeOH/Et₂O) 133

pale yellowcryst.(HCl salt)186-189(MeOH/Et₂O) 134

colorless cryst.(HCl salt)160-163(MeOH/Et₂O) 135

pale yellowcryst.(HCl salt)156-158(MeOH/Et₂O) 136

pale brownamorphous 137

pale brownamorphous 138

pale yellowcryst.(HCl salt)206-210(Me OH/Et₂O) 139

pale brownpowder178-181(MeOH/iso-Pr₂O) IR (CHCl₃) No. cm⁻¹ ¹H-NMR(CDCl₃) 1 HCl salt: KBr 1.46-1.80(4H, m), 2.10(3H, s), 2.15 & 2.16(3H,each s), 3424, 2940, 2805, 2.17 & 2.20(3H, each s), 2.59-2.78(2H, m),2.87 & 2.93 1642, 1489, 1418, (3H, each s), 3.09-3.18(2H, m), 3.34(2H,brs), 3.90 & 1321, 1298, 1284, 4.48-4.64(1H, m), 4.56 & 4.61(2H, eachs), 6.55 & 6.60 1140, 1100 (1H, each a) 2 3019, 2935, 1624, 1.54(3H, d),1.58-1.64(4H, m), 2.10(3H, a), 2.12 & 1484, 1420, 1377, 2.13(3H, eachs), 2.17(3H, a), 2.56(1H, m), 2.72(1H, m), 1320, 1251, 1137, 2.82 &2.87(3H, each s), 3.05-3.13(2H, m), 3.33(2H, brs), 1110, 1087, 4.56 &4.55(1H, m), 4.76-4.86(1H, m), 6.46 & 6.51 1035, 846 (1H, each s) 33374, 2939, 1612, 1.35-1.75(4H, m), 1.55 & 1.56(6H, s), 2.07, 2.09, 2.14& 1483, 1383, 1364, 2.16(9H, each s), 2.50-2.60 & 2.70-2.82(2H, m), 2.85& 3.13 1319, 1257, 1157, (3H, each s), 3.00-3.20(2H, m), 3.20-3.45(2H,brs), 4.55- 1086, 1019, 804 4.85(1H, m), 6.34 & 6.39(1H, each s) 4 1701,1654, 1648, 1.43-1.84(4H, m), 2.18(3H, s), 2.23(3H, s), 2.56-2.83 1498,1319, (2H, m), 2.79 & 2.90(3H, each s), 3.05-3.21(2H, m), 3.39- 1051,929 3.52 & 4.47-4.64(1H, m), 4.06-4.39(2H, brs), 4.50 & 4.53(2H, eachs), 6.33(1H, s), 6.39(1H, s) 5 3394, 2953, 1654, 1.60-1.91(4H, m),2.04(3H, s), 2.17 & 2.20(6H, each s), 1484, 1417, 2.61-2.84(2H, m),2.91(3H, a), 3.12-3.56(4H, m), 1320, 1225, 3.83 & 4.63(1H, m), 4.34 &4.38(2H, each s), 6.25 & 6.39 1090, 1052 (1H, each s) 6 3020, 1636,1518, 1.59-1.74(4H, m), 2.67-2.75(2H, m), 2.84 & 2.95 1320, 1170, 1137,(3H, each s), 3.10-3.13(2H, m), 3.45(2H, brs), 3.77 & 1030, 929 3.79(3H,each s), 4.02 & 4.52(1H, m), 4.70 & 4.73(2H, each a), 6.27(1H, m),6.41(1H, m), 6.72(1H, m) 7 3019, 1624, 1518, 1.13 & 1.22(3H, each t),1.67-1.68(4H, m), 2.69-2.71(2H, 1466, 1438, 1320, m), 3.12(2H, m), 3.32& 3.39(2H, each q), 3.35 & 3.97 1169, 1137, (1H, m), 3.45(2H, bra), 3.77& 3.79(3H, each s), 4.71 (2H, s), 1031, 929 6.25-6.27(1H, m), 6.40 &6.44(1H, m), 6.71(1H, m) 8 3448, 1628, 1513, 1.05 & 1.14(3H, each t),1.55-1.68(4H, m), 2.56-2.75(2H, 1466, 1438, 1319, m), 3.05(2H, m), 3.20& 3.28(2H, each q), 3.69 & 3.72 1174, 1036, (3H, each s), 3.84 &4.26(1H, m), 4.63(2H, s), 6.41 & 929, 849 6.45(1H, each s), 6.71 &6.73(1H, each s) 9 3020, 1629, 1466, 1.21 (3H, m), 1.68-1.78(4H, m),2.08(3H, s), 2.24(3H, 1436, 1380, 1320, s), 2.27(3H, s), 2.72(2H, m),3.15(2H, m), 3.42(2H, m), 1087, 1037 3.55(2H, brs), 4.16-4.19(1H, m),4.45(2H, s) 10 3413, 2952, 1638, 1.37-1.79(4H, m), 2.12 & 2.14(6H, eachs), 2.28(6H, s), 1466, 1420, 2.52-2.62 & 2.69-2.78(2H, m), 2.75 &2.90(3H, each s), 1320, 1089 3.08-3.18(2H, m), 3.34-3.53 & 4.61 (3H, m),3.58 & 3.63 (2H, each s) 11 3416, 2931, 1670, 1.30-1.44(2H, m),1.92-2.02(2H, m), 2.12(3H, s), 1530, 1485, 1444, 2.15(3H, s), 2.18(3H,s), 2.67-2.78(2H, m), 3.07 1320, 1253, 1122 (2H, dt), 3.39(2H, brs),3.99(1H, m), 4.36(2H, s), 6.50(1H, s), 6.52-6.64(1H, brs) 12 3020, 2935,1670, 1.32-1.47(2H, m), 1.50(3H, d), 1.95(2H, m), 1522, 1484, 2.11(3H,s), 2.13(8H, s), 2.18(3H, s), 2.71-2.79 1320, 1107 (2H, m), 3.10(2H, m),3.39(2H, brs), 3.94(1H, m), 4.44(1H, q), 6.47(1H, s), 6.56(1H, brs) 133417, 2935, 1654, 1.30-1.50(2H, m), 1.43(6H, s), 1.90-2.05(2H, m), 1518,1483, 1378, 2.10(3H, s), 2.11(3H, s), 2.15(3H, s), 2.68-2.80 1319, 1253,1155, (2H, m), 3.05-3.15(2H, dt, J=2.4Hz, 12.7Hz), 1079, 1014,3.30-3.60(2H, brs), 3.85-4.00(1H, m), 6.56(1H, s), 954, 806 6.90(1 H,brs) 14 3448, 1654, 1636, 1.10-1.29(3H, m), 1.44-1.78(4H, m), 2.10(3H,s), 1466, 1438, 2.16(3H, s), 2.17 & 2.21(3H, each s), 2.54-2.77(2H, m),1320, 1117 3.08-3.18(2H, m), 3.23-3.51(4H, m), 3.89 & 4.39 (1H, m), 4.57& 4.58(2H, each s), 6.55 & 6.60(1H, each s) 15 3448, 2937, 1624,1.07-1.11(3H, m), 1.52 & 1.55(3H, each d), 1.48-1.77 1466, 1433, 1376,(4H, m), 2.09(3H, s), 2.11 & 2.12(3H, each s), 2.18(3H, s), 1319, 1247,2.45-2.76(2H, m), 2.98-3.51 (6H, m), 4.14 & 4.38 1152, 1110 (1H, m),4.71 & 4.80(1H, each q), 6.50 & 6.53(1H, each s) 16 3008, 2951, 1632,1.61-1.76(4H, m), 2.08(3H, s), 2.24(3H, s), 2.26 1464, 1418, (3H, s),2.73-2.78(2H, m), 2.91 & 2.99(3H, each s), 1320, 1086, 3.14-3.16(2H, m),3.55(2H, brs), 4.18 & 4.59(1H, m), 1050, 1033 4.46(2H, s) 17 3408, 3018,1668, 1.45(2H, m), 1.99-2.03(2H, m), 2.08(3H, s), 1623, 1534, 1417,2.20(3H, s), 2.24(3H, s), 2.74(2H, m), 3.10(2H, m), 1320, 1108, 3.58(2H,brs), 4.01(1H, m), 4.26(2H, s), 6.96(1H, brs) 1089, 1045 18 3374, 1637,1.12-1.26(3H, m), 1.55-1.82(4H, m), 2.12 & 2.14 1420, 1382, (6H, eachs), 2.29(6H, s), 2.47-2.79(2H, m), 1256, 1098 3.08-3.24(2H, m), 3.19 &3.37(2H, each q), 3.28-3.53 & 4.49(3H, m), 3.60 & 3.61(2H, each s) 193224, 2944, 1632, 1.55(4H, m), 2.09(6H, s), 2.26(6H, s), 2.35 &2.72-2.76 1472, 1412, 1371, (2H, m), 2.72(3H, s), 2.84(3H, s),3.04-3.13(2H, m), 1328, 1159, 3.51(2H, brs), 3.76 & 3.79(2H, each s),4.58(1H, m) 1100, 1059 20 3004, 2952, 1628, 1.20 & 1.28(3H, each d),1.41-1.84(4H, m), 1458, 1412, 1320, 2.09 & 2.10(3H, each s), 2.11(3H,s), 2.23(3H, s), 1224, 1208, 2.25(3H, s), 2.52 & 2.73(2H, m), 2.69 &2.77(3H, each s), 1139, 1086 3.12(2H, m), 3.32 & 4.56(1H, m), 3.40(2H.brs), 3.94(1H, m) 21 3020, 2400, 1718, 1.33-1.46(2H, m), 1.51(9H, s),1.92-2.05(2H, m), 1064, 1522, 1482, 2.18(6H, s), 2.20(6H, s). 2.74(2H,dt), 3.09(2H, d), 1368, 1319, 1227, 3.49(2H, s), 3.50(1H, brs), 3.97(1H,m), 1205, 1162 5.86(1H, brs), 6.99(1H, d) 22 2924, 2779, 1640,1.50-1.80(4H, m), 2.19(6H, s), 2.24(6H, s), 1450, 1407, 2.60-2.90(2H,m), 2.76 & 2.80 & 2.89(9H, each s), 1370, 1329, 3.10-3.20(2H, m), 3.38&4.58(1H, m), 1285, 1064 3.67 & 3.71(2H, each s) 23 3020, 2101, 1654,1.52-1.79(4H, m), 2.12(3H, s), 2.17 & 2.19(3H, each s), 1648, 1482, 2.24& 2.25(3H, each s), 2.58 & 2.73(2H, m), 2.76 & 2.89 1438, 1407, (3H,each s), 3.08-3.20(2H, m), 3.37 & 4.59(1H, m), 1225, 1207 3.49(2H, brs),3.69 & 3.73(2H, each s), 4.36-4.65(1H, brs), 6.74 & 6.75(1H, each s) 243020, 2952, 1648, 1.53-1.81(4H, m), 2.21(3H, s), 2.27(3H, s), 2.28(3H,s), 1478, 1448, 1370, 2.61 & 2.69-2.87(2H, m), 2.77 & 2.80(3H, each s),2.81 1320, 1225, (6H, s), 3.14(2H, m), 3.39 & 4.60(1H, m), 3.71 & 3.761207, 1091 (2H, each s), 4.40-4.76(1H, brs), 6.78 & 6.79(1H, each s) 252944, 1641, 1.63-1.81(4H, m), 2.13(3H, s), 2.17 & 2.18(3H, each s),1582, 1408, 2.70-2.78(2H, m), 2.90 & 2.91(3H, each s), 3.16-3.22 1288,1243, (2H, m), 3.57 & 4.61(1H, m), 3.84 & 3.89(2H, each s), 1154, 11076.43 & 6.44(1H, each s), 6.54(1H, s) 26 CHCl₃:free base 1.34-1.89(4H,m), 2.67-2.80(2H, m), 2.90 & 2.93(3H, 1654, 1648, 1522, each s),3.09-3.27(2H, m), 3.54 & 4.60(1H, m), 3.63(2H, brs), 1508, 1458, 3.80 &3.85(2H, each d), 5.25(1H, m), 8.51 & 6.52 1420, 1225, (1H, each s),6.82(1H, s) 1206, 929 27 CHCl₃: free base 1.70-1.73(2H, m)1.78-1.88(2H,m), 2.72 & 2.81(2H, m), 3257, 2950, 2802, 2.90 & 2.96(3H, each s),3.24-3.31(2H, m), 3.41-3.52 & 2731, 1654, 1587, 4.64(1H, m),4.44-4.49(2H, m), 6.78(1H, m), 8.14(2H, s) 1522, 1435, 1378, 1310, 1142,1090 28 (KBr: CDCl₃) 3366, HCl salt (in CD₃OD) 1.88-2.09(2H, m),2.16-2.42(2H, m), 2938, 1647, 1538, 2.23(3H, s), 2.30(3H, s), 2.37(3H,s), 2.89 & 3.02(3H, s), 1489, 1456, 1418, 3.07-3.23(4H, m),3.26-3.41(2H, m), 3.67-3.84(2H, m), 1310, 1283, 1134, 4.21 & 4.60(1H,m), 4.86 & 4.96(2H, each s), 1101, 754, 703 6.73 & 6.83(1H, each s),7.23 & 7.41 (5H, m) 29 (KBr: CDCl₃) 2938, 1.66-2.02(4H, m), 2.11 (3H,s), 2.17&2.20(6H, each s) 1694, 1636, 1558, 2.29-2.49(2H, m),2.85-3.05(2H, m), 2.91 & 2.99(3H, each s), 1490, 1448, 1315, 3.14(2H,m), 3.36(2H, brs), 3.93&4.47(1H, m), 1132, 1102, 4.58&4.62(2H, each s),6.55&6.59(1H, each s), 948, 761 7.12(1H, m), 7.34(2H, m), 7.56(2H, d),8.94&9.03(1H, brs) 30 2938, 1694, 1624, free base (in CDCl₃)1.38-1.97(7H, m), 2.07-2.31 & 2.36-2.49 1600, 1557, 1490, (2H, m), 2.09& 2.10(3H, each s), 2.13 & 2.14(3H, each s), 1448, 1315, 1113, 2.18(3H,s), 2.84-3.03(2H, m), 2.87 & 2.97(3H, each s), 3.10 1074, 949, 760 &3.13(2H, each s), 3.34(2H, brs), 4.19 & 4.48(1H, m), 4.76- 4.87(1H, m),6.46 & 6.51(1H, each s), 7.07-7.14(1H, m), 7.30- 7.37(2H, m),7.49-7.63(2H, m), 8.93 & 9.02(1H, brs) 31 3416, 2936, 2690,1.52-1.60(3H, m), 1.84-1.97(2H, m), 2.10-2.34(2H, 1664, 1486, 1461, m),2.21 (3H, s), 2.25(3H, s), 2.30(3H, s), 2.85 & 3.06 1283, 1113, (3H,each s), 3.03-3.23(4H, m), 3.27-3.42(2H, m), 3.69- 1093, 704 3.78(2H,m), 4.27-4.58(1H, m), 5.07-5.22(1H, m), 6.52 & 6.59(1H, each s),7.25-7.33(5H, m) 32 3442, 2937, 1634, 1.53-1.63(3H, m), 1.82-1.94(2H,m), 2.16-2.39(2H, m), 1538, 1486, 1456, 2.21(6H, s), 2.22(3H, s),2.30(3H, s), 2.31(6H, s), 1284, 1112, 1034 2.36(3H, s), 2.86 & 3.08(3H,each s), 3.27-3.51(2H, m), 3.77(2H, m), 4.27-4.46 & 4.58(3H, m),5.14-5.24 & 5.33-5.43(1H, m), 6.55 & 6.69(1H, each s) 33 3398, 2936,1642, 1.54-1.63(3H, m), 1.84-1.96(2H, m), 2.23, 2.30 & 2.36 1486, 1417,1390, (9H, each s), 2.26-2.47(2H, m), 2.91 & 3.12(3H, s), 3.27- 1309,1286, 1215, 3.46(2H, m), 3.77-3.88(2H, m), 4.44 & 4.61(1H, m), 1113,1034, 836 4.73(2H, s), 5.17-5.38(1H, m), 6.56 & 6.66(1H, s), 7.57(1H,d), 7.67(1H, m), 7.84(1H, m), 7.99(1H, d), 8.14(1H, d), 8.44(1H, d) 343415, 2936, 1642, 1.91-2.10(2H, m), 2.13-2.47(2H, m), 2.21(6H, s), 1531,1487, 1461, 2.24(3H, s), 2.30(9H, s), 2.38(3H, s), 2.89 & 3.02 1284,1133, (3H, each s), 3.28-3.42(2H, m), 3.76(2H, m), 4.22 & 4.81 1104, 950(1H, m), 4.27-4.40(2H, m), 4.86 & 4.98(2H, each s), 6.74 & 6.85(1H, eachs) 35 3443, 2937, 1626, 1.53-1.60(3H, m), 1.73-1.90(2H, m),2.11-2.39(2H, 1486, 1450, 1324, m), 2.22(3H, s), 2.29(3H, s), 2.35(3H,s), 2.86 & 3.07(3H, 1288, 1215, 1114, each s), 2.90-3.15(2H, m),3.45-3.54(2H, m), 1023, 754 4.18-4.27 & 4.42-4.58(1H, m), 4.45 &4.52(2H, each s), 5.18 & 5.29(1H, each q), 6.53 & 6.65(1H, each s),7.53-7.63(2H, m), 7.73-7.83 (2H, m) 36 3441, 2972, 2731, 2.02-2.24(2H,m), 2.15 & 2.16(3H, each s), 2.20 & 2.21 1670, 1613, 1476, (3H, each s),2.26-2.42(2H, m), 2.75 & 2.92(3H, each s), 1409, 1217, 1045,3.24-3.37(2H, m), 3.46(1H, m), 3.60-3.79(2H, m), 4.51 & 843, 7654.52(2H, each s), 4.55(2H, s), 6.54(1H, s), 6.64(1H, s), 7.56(1H, dd),7.67(1H, d), 8.02(1H, m), 8.73(1H, m) 37 2924, 2616, 1651, 1.94-2.09(2H,m), 2.16-2.35(2H, m), 2.23(3H, s), 1481, 1331, 1307, 2.27(3H, 5),2.29(3H, s), 2.94(3H, 9), 3.063.43 1226, 1098, 1046 (6H, m),3.68-3.83(2H, m), 4.54(2H, s), 4.64(1H, m), 7.00(1H, s), 7.22-7.39(5H,m) 38 3422, 2940, 1622, 1.63(6H, s), 1.81-1.92(2H, m), 2.11-2.36(2H, m),1482, 1410, 1386, 2.20(3H, s), 2.29(3H, s), 2.30(3H, s), 2.88 & 3.101317, 1155, 1091, (3H, each s), 2.98-3.24(4H, m), 3.27-3.38(2H, m),3.60- 753, 703 3.80(2H, m), 4.61 & 4.87-4.98(1H, m), 6.45 & 6.49 (1H,each s), 7.22-7.39(5H, m) 39 3356, 3194, 2934, 1.87-2.09(2H, m),2.17-2.38(2H, m), 2.25(3H, s), 1691, 1634, 1533, 2.28(3H, s), 2.30(3H,s), 2.94(3H, s), 3.22-3.42(2H, m), 1486, 1397, 1304, 3.72-3.87(2H, m),4.14(2H, s), 4.56(2H, s), 4.67 1224, 1096, (1H, m), 6.94(1H, s),7.07(1H, s), 7.57(1H, s) 950, 880 40 3398, 2940, 2714, free base (inCDCl₃) 1.49-2.05(4H, m), 2.08-2.32(2H, m), 1649, 1493, 1456, 2.12(6H,s), 2.28(6H, s), 2.53-2.66(2H, m), 2.73-2.84 1421, 1107, 1069, (2H, m),2.75 & 2.90(3H, each s), 3.02-3.14(2H, m), 951, 755, 704 3.28-3.54(2H,brs), 3.34 & 4.56(1H, m), 3.59 & 3.62 (2H, each s), 7.16-7.23(3H, m),7.24-7.32(2H, m) 41 3415, 2958, 1690, free base (in CDCl₃) 1.48-1.98(4H,m), 2.12(6H, s), 2.28 1648, 1600, 1556, (6H, s), 2.20-2.50(2H, m), 2.80& 2.94(3H, each s), 3.00 1498, 1448, 1314, (2H, m), 3.12 & 3.15(2H, eachs), 3.33-3.54 & 4.56(3H, m), 1264, 950, 763 3.60 & 3.63(2H, each s),7.09-7.15(1H, m), 7.30-7.37(2H, m), 7.49-7.59(2H, m), 8.91 & 9.02(1H,brs) 42 2939, 2580, 1694, 1.43-1.73(2H, m), 1.56(6H, s), 1.76-1.90(2H,m), 2.06 & 1601, 1559, 1489, 2.08(3H, each s), 2.09 & 2.10(3H, each s),2.15 & 2.16 1448, 1315, 1156, (3H, s), 2.17-2.52(2H, m), 2.83-3.04(2H,m), 2.89 & 3.18 1092, 952, 759 (3H, each s), 3.08 & 3.14(2H, each s),3.34(2H, brs), 4.55 & 4.76(1H, m), 6.32 & 6.37(1H, each s), 7.11(1H, m),7.33(2H, m), 7.55(2H, m), 8.95 & 9.04(1H, brs) 43 3422, 3210, 2950,1.46-1.97(4H, m), 2.11(3H, s), 2.15 & 2.16(3H, each s), 1643, 1520,1489, 2.18(3H, s), 2.20(6H, s), 2.27-2.52(2H, m), 2.82- 1464, 1414,3.07(2H, m), 2.89 & 2.95(3H, each s), 3.16(2H, s), 3.35(2H, 1132, 1104brs), 3.94 & 4.48(1H, m), 4.58 & 4.62(2H, each s), 6.54 & 6.59(1H, eachs), 6.59(1H, s), 7.55(1H, s), 8.81 & 8.89(1H, brs) 44 3406, 2934, 1642,1.53-1.70(2H, m), 1.76-2.02(2H, m), 2.07-2.36 1600, 1487, 1417, (2H, m),2.10(3H, s), 2.14, 2.16 & 2.19(6H, each s), 2.88 & 1390, 1304, 1214,2.94(3H, each s), 2.92-3.04(2H, m), 3.34(2H, brs), 3.83 & 1131, 1099,3.84(2H, each s), 3.88 & 4.50(1H, m), 4.56 & 4.61(2H, s), 946, 842 6.54& 6.59(1H, each s), 7.52(1H, m), 7.60(1H, d), 7.70 (1H, m), 7.80(1H, d),8.07(1H, m), 8.12(1H, d) 45 3414, 2950, 1690, 1.69-1.99(4H, m), 2.11(3H,s), 2.16 & 2.20(6H, each s), 1645, 1581, 1540, 2.30-2.56(2H, m),2.36(3H, s), 2.89 & 2.97(3H, each s), 1488, 1463, 1289, 2.93-3.07(2H,m), 3.19(2H, s), 3.36(2H, brs), 3.96 1132, 1101, 1019, & 4.50(1H, m),4.58 & 4.62(2H, s), 6.55 & 6.59(1H, 950, 783 each s), 7.12-7.23(2H, m),7.99(1H, m), 9.21 & 9.31(1H, brs) 46 3416, 2904, 1684, 1.47(9H, s),1.65-2.00(4H, m), 2.11(3H, s), 2.15, 2.17 1646, 1534, 1488, & 2.19(6H,each s), 2.39-2.61(2H, m), 2.85 & 2.93(3H, each s), 1292, 1131, 1101,2.99-3.09(2H, m), 3.20(2H, s), 3.35(2H, brs), 3.95 & 4.51 950, 765 (1H,m), 4.57 & 4.62(2H, each s), 6.55 & 6.59(1H, each s), 9.35 & 9.42(1H,brs) 47 3417, 2950, 1648, 1.67-1.98(4H, m), 2.11(3H, s), 2.16, 2.17 &2.20(6H, each s), 1540, 1477, 1416, 2.24(6H, s), 2.36-2.54(2H, m), 2.87& 2.95(3H, each s), 1286, 1240, 1131, 3.04-3.16(2H, m), 3.20(2H, s),3.36(2H, brs), 3.95 & 4.50 1101, 1034, (1H, m), 4.58 & 4.62(2H, each s),6.55 & 6.60(1H, each s), 951, 778 7.03-7.17(3H, m), 8.54 & 8.64(1H, brs)48 3402, 2944, 1695, 1.47-1.87(4H, m), 1.56(6H, s), 2.07 & 2.08(3H, eachs), 2.09 1616, 1582, 1540, & 2.10(3H, each s), 2.15 & 2.16(3H, each s),2.27-2.57(2H, 1464, 1404, 1292, m), 2.34(3H, s), 2.87 & 3.16(3H, eachs), 2.84-3.07(2H, m), 1156, 1092, 1016, 3.13 & 3.19(2H, each s),3.34(2H, brs), 4.60 & 4.79(1H, m), 952, 782 6.32 & 6.37(1H, each s),7.10-7.18(2H, m), 7.94-8.06(1H, m), 9.25 & 9.31 (1H, brs) 49 3384, 2968,1684, 1.38-1.73(2H, m), 1.45(9H, s), 1.55 & 1.56(6H, each s), 1.77-1624, 1534, 1483, 1.88(2H, m), 2.07 & 2.08(3H, s), 2.10(3H, s), 2.14 &2.17 1404, 1157, 1089, (3H, each s), 2.35 & 2.55(2H, m), 2.84 & 3.13(3H,each s), 952, 7642 2.90-3.09(2H, m), 3.14 & 3.20(2H, each s), 3.34(2H,brs), 4.36 & 4.78(1H, m), 6.32 & 6.36(1H, each s), 7.07-7.13 & 7.20-7.27(2H, m), 7.38(1H, d), 7.90-8.02(1H, m), 9.38 & 9.43(1H, brs) 50 2939,2604, 1690, 1.47-1.89(4H, m), 1.55 & 1.57(6H, each s), 2.08 & 2.10 1637,1540, 1474, (6H, each s), 2.14 & 2.17(3H, each s), 2.21 & 2.23(6H, eachs), 1401, 1157, 1091, 2.18-2.34(1H, m), 2.50(1H, m), 2.86 & 3.15(3H,each s), 951, 775 2.94-3.17(2H, m), 3.15 & 3.21(2H, each s), 3.34(2H,brs), 4.58 & 4.79(1H, m), 6.33 & 6.37(1H, s), 7.05-7.15(3H, m), 8.56 &8.63(1H, brs) 51 3418, 2975, 1690, 1.20 & 1.28(3H, t), 1.651.95(4H, m),2.43(2H, m), 1646, 1556, 1511, 3.02(2H, m), 3.16(2H, s), 3.30-3.50(2H,m), 3.78 & 3.81 1447, 1404, 1354, (3H, each s), 3.97(1H, m), 4.72(2H,s), 6.51 & 6.54(1H, each 1267, 1178, s), 6.81 & 6.83(1H, each s),7.14(1H, t), 7.36(2H, m), 1072, 948 7.59(2H, m), 8.97 & 9.06(1H, brs) 523416, 2970, 1684, 1.15 & 1.21 (3H, each t), 1.71-1.92(4H, m), 2.21(6H,s), 1646, 1511, 1403, 2.29(3H, s), 2.45(2H, m), 3.08(2H, m), 3.21(2H,s), 1270, 1219, 1180, 3.30-3.50(2H, m), 3.78(1H, m), 3.79 & 3.80(3H,each s), 1074, 1035, 853 4.72(2H, brs), 6.51 & 6.55(1H, each s),6.82(1H, s), 6.92(2H, s), 8.48 & 8.55(1H, brs) 53 3383, 2938, 2714,1.47-2.26(6H, m), 2.09 & 2.10(3H, each s), 2.15, 2.17 & 2592, 1646,1489, 2.19(6H, each s), 2.87 & 2.93(3H, each s), 3.00-3.22(4H, m), 1456,1418, 1325, 3.33(2H, brs), 3.84 & 4.49(1H, m), 4.56 & 4.60(2H, each s),1285, 1134, 1104, 6.16-6.36(1H, m), 6.44-6.65(2H, m), 7.18-7.40 (5H, m)1031, 978, 942, 749 54 3416, 2939, 1647, 0.04-0.77(2H, m), 0.79-0.94(2H,m), 1.44-1.82(4H, m), 1.92- 1489, 1458, 1417, 2.23(2H, m), 2.09 &2.10(3H, each s), 2.14, 2.15 & 2.18(6H, 1323, 1303, 1287, each s), 2.54& 2.55(2H, each s), 2.80 & 2.86(3H, each s), 1244, 1134, 1098,2.94-3.10(2H, m), 3.35(2H, brs), 3.72 & 4.38(1H, m), 4.54 1030, 940, 704& 4.57(2H, each s), 6.52 & 6.57(1H, each s), 7.17(1H, m), 7.23-7.37(4H,m) 55 3416, 3214, 2950, 1.23-1.33(4H, m), 1.47-1.93(4H, m), 2.10(3H, s),1684, 1646, 1544, 2.15 & 2.19(6H, each s), 2.24(1H, m), 2.33(1H, m),2.82-2.93 1489, 1457, 1418, (2H, m), 2.88 & 2.95(3H, s), 2.99 & 3.00(2H,each s), 1323, 1303, 1285, 3.35(2H, brs), 3.87 & 4.42(1H, m), 4.57 &4.60(2H, each 1132, 1102, 1030, s), 6.54 & 6.58(1H, each s),7.15-7.33(5H, m), 7.62 & 760, 700 7.68(1H, brs) 56 2942, 2860, 2593,1.81-2.33(6H, m), 2.10(3H, s), 2.15, 2.17 & 2.20(6H, each 1694, 1642,1597, s), 2.87 & 2.94(3H, each s), 3.03-3.13(2H, m), 3.81 & 3.83 1488,1451, 1306, (2H, each s), 3.87 & 4.51 (1H, m), 4.57 & 4.61(2H, each s),1260, 1230, 1132, 6.45 & 6.60(1H, each s), 7.46(2H, m), 7.57(1H, m),7.98 1102, 946 (2H, m) 57 1646, 1515, 1486, 1.14 & 1.23(3H, each t),1.74-1.98(4H, m), 2.19(6H, s), 1445, 1400, 1166, 2.27(3H, s), 2.43(2H,m), 3.07(2H, m), 3.18(2H, s), 3.31 & 1138, 1020 3.40(2H, each q),3.45(2H, brs), 3.78 & 3.79(3H, each s), 4.01 & 4.16(1H, m), 4.70 &4.72(2H, each s), 6.27 & 6.29 (1H, m), 6.40 & 6.44(1H, m), 6.71 &6.73(1H, each s), 6.90(2H, s), 8.47 & 8.54(1 H, brs) 58 1645, 1515,1446, 1.67-1.92(4H, m), 2.18(6H, s), 2.27(3H, s), 2.45(2H, 1350, 1296,1166, m), 2.85 & 2.97(3H, each s), 3.07(2H, m), 3.18(2H, s), 1139, 1061,1023 3.46(2H, brs), 3.78 & 3.79(3H, each s), 4.03 & 4.46(1H, m), 4.71 &4.74(2H, s), 6.27 & 6.29(1H, each d), 6.39 & 6.42 (1H, each d), 6.72 &6.74(1H, each s), 6.90(2H, s), 8.47 & 8.52(1H, brs) 59 1694, 1646, 1599,1.69(2H, m), 1.85(2H, m), 2.42(2H, m), 2.89 & 3.01 1557, 1515, 1447,(3H, each s), 2.97-3.01(2H, m), 3.13(2H, s), 3.45((2H, brs), 1166, 1139,3.76 & 3.80(3H, each s), 4.01 & 4.43(1H, m), 4.71 & 4.73 1061, 1021 (2H,each s), 6.27 & 6.29(1H, m), 6.39 & 6.40(1H, m), 6.72(1H, m), 7.12(1H,d), 7.34(2H, t), 7.56(2H, d), 8.97 & 9.02(1H, brs) 60 3411, 2963, 1687,1.38-1.97(7H, m), 1.46(9H, s), 2.10(3H, s), 2.12 & 2.14(3H, 1638, 1534,1486, each s), 2.17 & 2.18(3H, each s), 2.36(1H, m), 2.47-2.57 1415,1291, 1113, (1H, m), 2.81 & 2.92(3H, each s), 3.02(2H, m), 3.16 & 3.191090, 951, 764 (2H, each s), 3.34(2H, brs), 4.22 & 4.52(1H, m), 4.79 &4.83(1H, each q), 6.46 & 6.51(1H, each s), (1H,brs) 7.19-7.27(1H, m),7.38(1H, dd), 7.97(1H, d), 9.33 & 9.41 61 3424, 2942, 1688,1.41-1.98(7H, m), 2.10 & 2.11(3H. each s), 2.13 & 2.14(3H, 1634, 1538,1478, each s), 2.17 & 2.18(3H, each s), 2.22 & 2.23(6H, each s), 2.25-1416, 1286, 1240, 2.53(2H, m), 2.83 & 2.93(3H, each s), 2.98-3.12(2H,m), 3.15- 1113, 1074, 1035 3.23(2H, m), 3.34(2H, brs), 4.23 & 4.50(1H,m), 4.80 & 4.83 (1H, each q), 6.46 & 6.52(1H, each s), 7.05-7.15(3H, m),8.48-8.67(1H, m) 62 3410, 2937, 2712, 1.25-2.03(6H, m), 1.54(3H, t),2.09(3H, s), 2.12 & 2.13(3H, 1638, 1487, 1452, each s), 2.17 & 2.18(3H,each s), 2.82 & 2.92(3H, each s), 1413, 1323, 1283, 3.04(2H, m),3.09-3.18(2H, m), 3.31(2H, brs), 4.11 & 4.50 1244, 1215, 1113, (1H, m),4.73-4.92(1H, m), 6.17-6.32(1H, m), 6.43-6.58 1075, 976, 749 (2H, m),7.22(1H, m), 7.30(2H, m), 7.37(2H, m) 63 3411, 2937, 1648, 0.75-0.86(1H,m), 0.91-1.02(1H, m), 1.15-1.27(1H, m), 1605, 1486, 1460, 1.32-2.22(7H,m), 1.54(3H, t), 2.09(3H, s), 2.12 & 2.1 3(3H, 1417, 1323, 1285, eachs), 2.14 & 2.16(3H, each s), 2.26-2.57(2H, m), 2.81 & 1243, 1115, 1032,2.90(3H, each s), 2.98-3.16(2H, m), 3.32(2H, brs), 4.10 & 759, 7004.47(1H, m), 4.79(1H, m), 6.45 & 6.50(1H, each s), 7.03 (2H, m),7.14(1H, m), 7.20-7.29(2H, m) 64 3411, 3203, 2940, 1.19-1.33(4H, m),1.47-1.90(7H, m), 2.07-2.38(2H, m), 2.10 2590, 1688, 1638, (3H, s), 2.12& 2.13(3H, each s), 2.16 & 2.17(3H, each s), 1545, 1486, 1458,2.75-2.90(2H, m), 2.83 & 2.93(3H, each s), 2.94-3.03(2H, 1416, 1322,1284, m), 3.34(2H, brs), 4.15 & 4.42(1H, m), 4.73-4.86(1H, 1110, 1030,m), 6.45 & 6.50(1H, each s), 7.15-7.32(5H, m), 7.59 & 7.67 760, 700 (1H,brs) 65 3368, 2932, 2874, 1.47-1.98(4H, m), 2.10(3H, s), 2.15, 2.16 &2.20(6H, each 2573, 1647, 1598, s), 2.29-2.60(4H, m), 2.84-3.12(2H, m),2.88 & 2.94 1492, 1459, 1417, (3H, each s), 3.34(2H, brs), 3.88 &4.49(1H, m), 3.98(2H, 1293, 1244, 1137, d), 4.02-4.12(1H, m), 4.57 &4.61 (2H, each s), 6.54 & 6.59 1109, 1038, 757 (1H, each s),6.87-7.01(3H, m), 7.24-7.32(2H, m) 66 3392, 3214, 2590, 1.15-1.23(2H,m), 1.25-1.32(1H, m), 1.50-1.93(4H, 1672, 1556, 1487, m), 2.06(1H, m),2.10(3H, s), 2.15(3H, s), 2.19(3H, s), 1461, 1415, 1286, 2.24(1H, m),2.33(1H, m), 2.81-3.06(2H, m), 2.88 & 1131, 1103, 1031, 2.96(3H, eachs), 3.00(2H, s), 3.35(2H, brs), 3.88 & 4.42 951, 700 (1H, m), 4.57 &4.60(2H, each s), 6.54 & 6.58(1H, each s), 7.13-7.33(6H, m) 67 3982,2939, 2586, 1.37-1.67(2H, m), 1.56(6H, s), 1.73-1.86(2H, m), 1.88- 1618,1482, 1410, 2.20(2H, m), 2.05 & 2.08(3H, s), 2.09(3H, s), 2.13 & 1156,1096, 978, 2.16(3H, each s), 2.85 & 3.13(3H, each s), 2.92-3.19(4H, 950,748 m), 3.32(2H, brs), 4.59 & 4.70(1H, m), 6.17-6.35(1H, m), 6.33 &6.38(1H, each s), 6.48 & 6.52(1H, each d), 7.22(1H, m), 7.30(2H, m),7.36(2H, m) 68 3382, 2939, 2587, (HCl salt in CD₃OD): 1.12(4H, m),1.43-1.77(2H, m), 1622, 1482, 1409, 1.60(6H, s), 1.99-2.15(2H, m), 2.18& 2.19(3H, each s), 1318, 1156, 1089, 2.28(6H, s), 2.79 & 3.01(3H, eachs), 2.84-3.15(2H, m), 1029, 763, 704 3.46-3.66(2H, m), 3.49(2H, s), 4.52& 4.74-4.86(1H, m), 6.41 & 6.45(1H, each s), 7.30(1H, m), 7.39(2H, m),7.44- 7.57(2H, m) 69 3416, 3194, 2946, 1.19-1.32(4H, m), 1.37-1.84(10H,m), 2.03-2.20 & 2.34 2590, 1688, 1630, (2H, m), 2.07(3H, s), 2.10(3H,s), 2.14(3H, s), 2.72-2.92 1548, 1482, 1460, (2H, m), 2.86 & 2.95(2H,each s), 3.00 & 3.14(3H, each s), 1403, 1321, 1156, 3.34(2H, brs), 4.49& 4.71(1H, m), 6.31 & 6.36(1H, each s), 1092, 1029, 7.15-7.32(5H, m),7.61 & 7.68(1H, brs) 953, 759 70 3381, 2947, 2731, (HCl salt in CD₃OD):1.09-1.19(4H, m), 1.79-1.96(2H, 2568, 1649, 1582, m), 2.07-2.20(2H, m),2.29, 2.31, 2.35 & 2.37(12H, each s). 1496, 1450, 1417, 2.85 & 2.90(3H,each s), 3.01-3.25(2H, m), 3.50 & 3.51 1104, 1065, 1030, (2H, each s),3.55-3.68(2H, m), 3.93 & 4.57(1H, m), 766, 704 4.21 & 4.44(2H, each s),7.25-7.57(5H, m) 71 3416, 2968, 2596, 1.16-1.30(3H, m), 1.76(2H, m),1.82-2.08(2H, m), 1693, 1629, 1600, 2.10(3H, s), 2.16 & 2.21 (6H, eachs), 2.36(2H, m), 2.99 1556, 1490, 1448, (2H, m), 3.13(2H, s), 3.25-3.51(4H, m), 3.92 & 4.15 1316, 1236, 1131, (1H, m), 4.58 & 4.59(2H, each s),6.55 & 6.60(1H, each s), 1111, 1032 7.12(1H, t), 7.34(2H, t), 7.55(2H,m), 8.93 & 9.06(1H, brs) 72 1687, 1638, 1546, 1.28(4H, m), 1.70-1.92(4H,m), 2.07(3H, s), 2.24(3H, 1498, 1456, 1417, s), 2.25(3H, s), 2.34(2H,m), 2.89(2H, m), 2.92(2H, 1320, 1304, s), 3.01 & 3.02(3H, each s),3.56(2H, brs), 4.20 & 4.50 1100, 1031 (1H, m), 4.46(2H, s),7.16-7.21(1H, m), 7.24-7.30 (4H, m), 7.66 & 7.70(1H, brs) 73 1692, 1634,1556, 1.25-1.27(3H, m), 1.82-2.03(4H, m), 2.08(3H, s), 1500, 1448, 1411,2.25(3H, s), 2.26(3H, s), 2.43(2H, m), 3.01 (2H, m), 1317, 1106, 10503.15(2H, s), 3.41-3.45(2H, m), 3.56(2H, brs), 4.23 (1H, m), 4.45(2H, s),7.12(1H, t), 7.34(2H, t), 7.58 (2H, d), 9.01 & 9.08(1H, brs) 74 3406,2938, 2596, 1.15 & 1.20(3H, m), 1.66-2.24(6H, m), 2.10(3H, s), 1650,1485, 1460, 2.15(3H, s), 2.17 & 2.20(3H, each s), 3.05(2H, m), 3.141324, 1284, 1215, (2H, m), 3.25-3.43(4H, m), 3.42 & 1133, 1111, 1033,4.58(2H, s), 6.26(1H, m), 6.51(1H, m), 6.54 & 6.60 977, 945 (1H, eachs), 7.22(1H, t), 7.30(2H, t), 7.37(2H, d) 75 3405, 3193, 2974, 1.15 &1.16(3H, each t), 1.37-1.94(7H, m), 1.95-2.44(2H, 1695, 1623, 1556, m),2.09(3H, s), 2.13(3H, s), 2.17 & 2.18(3H, each s), 2.85- 1489, 1448,1315, 3.02(2H, m), 3.09 & 3.13(2H, each s), 3.20-3.52(4H, m), 1259,1215, 1109, 4.05-4.24(1H, m), 4.73 & 4.80(1H, each q), 6.51 & 6.53 1030,949 (1H, each s), 7.11(1H, t), 7.33(2H, t), 7.55(2H, m), 8.91 & 9.07(1H,brs) 76 3402, 2945, 2736, 1.081.24(3H, m), 1.58-2.02(4H, m),2.06-2.23(2H, 2558, 1643, 1584, m), 2.12 & 2.14(6H, each s), 2.29(6H,s), 2.53-2.67(2H, m), 1460, 1384, 1290, 2.78(2H, m), 3.07(2H, m), 3.20 &3.38(2H, each q), 3.27- 1112, 1072, 954, 3.57 & 4.49(3H, m), 3.61 (2H,s), 7.15-7.34(5H, m) 754, 702 77 3410, 2937, 2592, 1.05-1.16(3H, m),1.33-2.26(6H, m), 1.52 & 1.55(3H, each d), 1642, 1485, 1460, 2.09(3H,s), 2.11 & 2.12(3H, s), 2.18(3H, s), 2.90-3.53 1431, 1377, 1323, (6H,m), 3.11 & 3.15(2H, each d), 4.11 & 4.42(1H, m), 1285, 1215, 1132, 4.72& 4.79(1H, each q), 6.25(1H, m), 6.43-6.62(2H, m), 1112, 1028, 7.23(1H,t), 7.27-7.40(4H, m) 976, 946 78 3406, 2939, 2710, 1.16(3H, m),1.45-2.20(6H, m), 2.12 & 2.14(6H, each s), 2555, 1646, 1580, 2.28(6H,s), 3.05(2H, m), 3.10-3.23(2H, m), 3.27-3.63 1450, 1384, 1278, &4.50(4H, m), 3.37 & 3.48(2H, each q), 3.61 (2H, s), 1211, 1113, 1072,6.16-6.33(1H, m), 6.50 & 6.52(1H, each d), 7.22(1H, t), 980, 9467.31(2H, t), 7.37(2H, d) 79 3442, 2941, 1684, 1.56(6H, s), 1.40-1.75(2H,m), 1.75-1.95(2H, m), 2.06, 1618, 1534, 1489, 2.08, 2.09, 2.10, 2.14 &2.1 6(9H, each s), 2.28 & 2.49 1399, 1156, 1081 (2H, m), 2.86 & 2.88(2H,each s), 2.95 & 3.15(3H, s), 2.95-3.15(2H, m), 3.20-3.45(2H, m),3.85-4.10(2H, m), 4.61 & 4.76(1H, m), 6.32 & 6.37(1H, s), 6.79(1H, s),8.35 & 8.36(1H, s), 9.59 & 9.64(1H, s) 80 3418, 2936, 2587, 1.42(6H, s),1.45-1.70(2H, m), 1.95-2.10(2H, m), 1654, 1522, 1480, 2.09(3H, s), 2.11(3H, s), 2.14(3H, s), 2.15-2.30(2H, 1312, 1156, 1094, m), 2.85-2.95(2H,m), 3.15(2H, d), 3.42(2H, brs), 945, 749, 695 3.87(1H, m), 6.26(1H, dt),6.51(1H, d), 6.56(1H, s), 81 3418, 2932, 2580, 0.70-0.73(2H, m),0.84-0.88(2H, m), 1.41(6H, s), 1668, 1532, 1482, 1.35-1.50(2H, m),1.80-1.90(2H, m), 2.10(3H, s), 1157, 1107, 701 2.11(3H, s), 2.14(3H, s),2.04-2.20(2H, m), 2.55(2H, s), 2.75-2.95(2H, m), 3.41(2H, brs), 3.79(1H,m), 6.54(1H, s), 6.83(1H, d), 7.16(1H, t), 7.25(2H, t), 7.32(2H, d) 823360, 2968, 2607, 1.44(6H, s), 1.45-1.70(2H, m), 2.00-2.25(2H, m), 1087,1654, 1560, 2.11(3H, 5), 2.12(3H, s), 2.17(3H, s), 2.40-2.55(2H, 1534,1500, 1448, m), 2.80-3.05(2H, m), 3.13(2H, s), 3.35-3.55(2H, brs), 1316,1157, 1098, 3.85-4.00(1H, m), 6.55(1H, s), 6.92(1H, d), 7.10 950, 762,692 (1H, t), 7.33(2H, 0, 7.55(2H, d) 83 3424, 2936, 2495, 1.45-1.63(2H,m), 1.51 (3H, d), 2.00(2H, m), 1684, 1601, 1556, 2.13(3H, s), 2.14(3H,s), 2.21 (3H, s), 2.44(2H, m), 1500, 1448, 1316, 2.83(2H, m), 3.11(2H,s), 3.41 (2H, brs), 3.90(1H, m), 1148, 1116 4.45(1H, q), 6.48(1H, s),6.57 & 6.59(1H, brs), 7.10 (1H, t), 7.33(2H, t), 7.55(2H, d), 9.04(1H,brs) 84 3424, 3193, 2938, 1.41-1.51(2H, m), 1.50(3H, d), 1.94(2H, m),2.06- 2806, 2594, 1680, 2.23(2H, m), 2.11(3H, s), 2.13(3H, s), 2.18(3H,s), 1590, 1552, 1486, 2.85(2H, m), 3.13(2H, d), 3.38(2H, brs), 3.86(1H,m), 1153, 1118 4.44(1H, q), 6.24(1H, dt), 6.48(1H, s), 6.50(1H, d),6.54(1H, brs), 7.20-7.23(1H, m), 7.30(2H, t), 7.35-7.37 (2H, m) 85 3402,3247, 2946, 1.48-1.66(2H, m), 2.00-2.09(2H, m), 2.13(3H, s), 2592, 1688,1600, 2.16(3H, s), 2.21(3H, s), 2.38-2.57(2H, m), 2.86(2H, 1556,1491,1448, m), 3.13(2H, s), 3.41 (2H, brs), 3.97(1H, m), 4.38(2H, 1315,1128,949 s), 6.50(1H, s), 6.60(1H, brs), 7.11(1H, t), 7.33(2H, m), 7.58(2H,d), 9.04(1H, brs) 86 3326, 2934, 2518, 1.46-1.75(2H, m), 1.94-2.03(2H,m), 2.09-2.25(2H, 1662, 1547, 1486, m), 2.11(3H, s), 2.15(3H, s),2.17(3H, s), 2.78-2.99 1451, 1326, 1285, (2H, m), 3.15(2H, d), 3.39(2H,brs), 3.93(1H, m), 1238, 1214, 1130, 4.36(2H, s), 6.26(1H, dt),6.47-6.63(2H, m), 6.49 976, 942 (1H, s), 7.22(1H, t), 7.30(2H, m),7.37(2H, d) 87 3404, 2936, 2579, 0.64-0.74 & 0.81-0.90(4H, m), 1.06(3H,m), 1.19-1.28(1H, m), 1642, 1485, 1461, 1.44-1.77(2H, m), 1.50 &1.52(3H, each d), 1.82-1.91(2H, m), 1432, 1376, 1322, 1.97-2.23(1H, m),2.08 & 2.09(3H, each s), 2.10 & 2.11(3H, 1286, 1245, 1215, each s),2.16(3H, s), 2.51 & 2.55(2H, each s), 2.87-3.05(2H, 1112, 1027 m),3.09-3.55(4H, m), 3.98 & 4.29(1H, m), 4.69 & 4.76(1H, each q), 6.48 &6.50(1H, each s), 7.13-7.20(1H, m), 7.22-7.38(4H, m) 88 3403, 2944,2728, 0.66-0.76 & 0.82-0.88(4H, m), 1.06-1.16(3H, m), 2563, 1646, 1581,1.44-1.76, 1.81-1.92 & 1.97-2.30(6H, m), 2.12 & 2.14(6H, each 1460,1432, 1296, s), 2.24 & 2.27(6H, each s), 2.52 & 2.56(2H, each s), 2.96-1113, 1069, 3.05(2H, m), 3.11 & 3.30(2H, each q), 3.24 & 4.37(1H, m),1028, 943 3.34-3.65(2H, brs), 3.57(2H, s), 7.13-7.22(1H, m),7.23-7.36(4H, m) 89 3402, 2944, 2591, 1.65-1.77(2H, m), 1.78-1.90(1H,m), 1.90-2.03(1H, m), 2.10 1692, 1640, 1530, (3H, s), 2.16 & 2.20(6H,each s), 2.33-2.55(2H, m), 2.88 & 1486, 1385, 1302, 2.95(3H, each s),2.92-3.03(2H, m), 3.15 & 3.18(2H, each s), 1285, 1132, 1100 3.36(2H,brs), 3.94 & 4.51(1H, m), 3.99(2H, brs), 4.58 & 4.61 (2H, each s), 6.55& 6.59(1H, each s), 6.81(1H, s), 8.36 & 8.37(1H, each s), 9.56 &9.64(1H, brs) 90 3416, 2939, 2600, 0.68-0.72 & O.83-0.86(4H, m),1.24-1.26 & 1.39-1.42 1634, 1486, 1416, (2H, m), 1.51 & 1.53(3H, eachd), 1.56-1.77(2H, m), 1.89 & 1323, 1112, 1028, 2.04(2H, m), 2.09(3H, s),2.11 & 2.12(3H, each s), 2.15(3H, 763, 704 s), 2.52 & 2.55(2H, each s),2.76 & 2.84(3H, each s), 2.97(2H, m), 3.31 (2H, brs), 4.00 & 4.38(1H,m), 4.76 & 4.79(1H, each q), 6.43 & 6.49(1H, each s), 7.14-7.21(1H, m),7.23-7.32(4H, m) 91 3258, 1657, 1601, 1.69(2H, m), 2.09(3H, s),2.09-2.10(2H, m), 2.22(3H, 1556, 1500, 1448, s), 2.25(3H, s), 2.49(2H,m), 2.91 (2H, m), 3.15(2H, s), 1408, 1315, 1106, 3.59(2H, brs), 4.01(1H,m), 4.27(2H, s), 7.00(1H, brs), 953, 756, 694 7.11(1H, t), 7.34(2H, t),7.57(2H, d), 9.09(1H, brs) 92 3424, 2948, 1692, 1.73-1.84(4H, m),2.08(3H, s), 2.25(6H, s), 2.49(2H, 1634, 1534, 1497, m), 2.92 & 3.03(3H,each s), 2.99-3.03(2H, m), 3.1 6(2H, s), 1456, 1398, 1319, 3.55(2H,brs), 3.99(2H, brs), 4.27 & 4.55(1H, m), 4.47 1304, 1101, (2H, s),6.81(1H, s), 8.38(1H, s), 9.63 & 9.66(1H, brs) 1049, 950 93 3208, 2972,1632, 1.24(3H, m), 1.85-2.03(4H, m), 2.07(3H, s), 2.21 (6H, 1549, 1520,1463, s), 2.25(3H, s), 2.26(3H, s), 2.45(2H, m), 3.03(2H, m), 1412,1320, 3.16(2H, s), 3.39 & 3.44(2H, m), 3.56(2H, brs), 4.25 1104, 952(1H, m), 4.46(2H, s), 4.70(1H, s), 6.62(1H, s), 7.61 (1H, s), 8.88 &8.95(1H, brs) 94 3402, 2944, 2726, 0.77-0.86, 0.92-1.01 & 1.10-1.28(3H,m), 1.14 & 1.16(3H, 2554, 1643, 1464, each t), 1.42-2.02(5H, m),2.04-2.42(3H, m), 2.12 & 2.14 1426, 1391, (6H, each s), 2.24 & 2.28(6H,each s), 2.50 & 2.53(1H, each 1290, 1073 dd), 3.04-3.16(2H, m), 3.18 &3.36(2H, each q), 3.23-3.52 (2H, brs), 3.29 & 4.46(1H, m), 3.60(2H, s),7.01-7.07(2H, m), 7.14(1H, t), 7.20-7.29(2H, m) 95 3416, 2943, 1672,0.77-0.86, 0.92-1.00 & 1.16-1.28(3H, m), 1.49-1.63 1544, 1486, 1460,(2H, m), 1.67(1H, m), 1.92-2.02(2H, m), 2.11(3H, s), 1390, 1326, 1284,2.15(3H, s), 2.17(3H, s), 2.09-2.27(2H, m), 2.36(1H, 1240, 1215, dd),2.50(1H, dd), 2.92(2H, m), 3.38(2H, brs), 3.91(1H, 1128, 951 m),4.36(2H, s), 6.48(1H, s), 6.56(1H, brs), 7.04(2H, d), 7.14(1H, t),7.18-7.27(2H, m) 96 3402, 2944, 2592, 0.71(2H, m), 0.85(2H, m), 1.41(2H, m), 1.75-1.90(2H, 1672, 1590, 1545, m), 2.07-2.22(2H, m), 2.11(3H,s), 2.14(3H, s), 2.16 1487, 1460, 1325, (3H, s), 2.55(2H, s), 2.82(2H,m), 3.38(2H, brs), 3.84 1286, 1241, (1H, m), 4.33(2H, s), 6.47(1H, s),6.50(1H, brs), 7.16 1132, 1027 (1H, t), 7.22-7.28(2H, m), 7.29-7.34(2H,m) 97 2944, 2506, 1663, 1.46-1.63(2H, m), 1.94-2.03(2H, m), 2.12(3H, s),1588, 1545, 1487, 2.15(3H, s), 2.18(3H, s), 2.23(2H, m), 2.59(2H, m),1456, 1314, 1282, 2.79(2H, m), 2.89(2H, m), 3.39(2H, brs), 3.93(1H, m),1239, 1214, 1129 4.37(2H, s), 6.49(1H, s), 6.58(1H, brs), 7.16-7.22(3H,m), 7.24-7.34(2H, m) 98 3417, 2932, 1672, 1.43(6H, s), 1.45-1.70(2H, m),2.03-2.20(2H, m), 1534, 1477, 1157, 2.10(3H, s), 2.12(3H, s), 2.15(3H,s), 2.22(6H, s), 1095, 953, 774 2.53(2H, m), 2.90-3.05(2H, m), 3.20(2H,s), 3.42(2H, brs), 3.93(1H, m), 6.55(1H, s), 6.92(1H, d), 7.08(3H, m),8.61 (1H, brs) 99 3416, 2934, 2586, 0.78-0.85(1H, m), 0.93-0.98(1H, m),1.18-1.28(1H, m), 1.41 1654, 1522, 1477, (3H, s), 1.42(3H, s),1.45-1.63(2H, m), 1.67(1H, m), 1.92- 1155, 1094, 700 2.02(2H, m),2.09(3H, s), 2.10(3H, s), 2.14(3H, s), 2.15- 2.28(2H, m), 2.37(1H, dd),2.50(1H, dd), 2.85-3.05(2H, m), 3.35-3.50(2H, brs), 3.84(1H, m),6.56(1H, s), 6.89 (1H, d), 7.04(2H, d), 7.13(1H, t), 7.20-7.31(2H, m)100 3424,2968, 1676, 1.43 & 1.44(15H, each s), 1.45-1.65(2H, m),1.95-2.10(2H, 1534,1482, 1157, m), 2.10 & 2.12(6H, s), 2.16(3H, s),2.45-2.65(2H, m), 1091, 953, 764 2.85-3.00(2H, m), 3.19(2H, s),3.35-3.50(2H, brs), 3.85- 4.00(1H, m), 6.56(1H, s), 6.93(1H, d),7.11(1H, t), 7.20- 7.30(1H, m), 7.38(1H, d), 7.95(1H, d), 9.36(1H, brs)101 3419, 2942, 2580, 0.70, 0.84 & 1.35(6H, m), 1.47(3H, d), 1.80(2H,m), 1691, 1666, 1592, 2.05-2.16(2H, m), 2.10(3H, s), 2.12(3H, s), 2.16(3H, 1487, 1459, 1428, s), 2.52(2H, s), 2.75-2.83(2H, m), 3.37(2H,brs), 3.76 760, 701 7.17(1H, t), 7.22-7.26(2H, m), 7.30-7.32(2H, m) 1023418, 1684, 1541, 1.21-1.30(4H, m), 1.41-1.55(2H, m), 1.50(3H, d), 1498,1486, 1460, 1.94(2H, m), 2.12(3H, s), 2.14(3H, s), 2.19(3H, s), 1324,1149, 1116, 2.33(2H, m), 2.65-2.73(2H, m), 2.97(2H, s), 3.40(2H, 1030,950 brs), 3.85(1H, m), 4.43(1H, q), 6.46(1H, s), 6.53 (1H, brs),7.18-7.31 (5H, m), 7.67 (1H, brs) 103 2938, 1634, 1599, 1.54(3H, d),1.56-1.88(4H, m), 2.10(3H, s), 2.13 & 2.14 1492, 1417, 1114, (3H, eachs), 2.17(3H, s), 2.24(2H, m), 2.53(2H, m), 2.83 1040, 759, 694 &2.92(3H, each s), 3.06(2H, m), 3.34(2H, brs), 3.97(2H, d), 4.03-4.06(1H,m), 4.15 & 4.47-4.53(1H, m), 4.77-4.85 (1H, m), 6.45 & 6.51(1H, each s),6.91-6.97(3H, m), 7.26- 7.31 (2H, m) 104 3402, 3217, 2945, 1.25, 1.28,1.46-1.64 & 1.93-2.03(8H, m), 2.12(3H, 1680, 1540, 1487, s), 2.15(3H,s), 2.19(3H, s), 2.36(2H, m), 2.73(2H, 1458, 1324, 1283, m), 2.99(2H,s), 3.40(2H, brs), 3.92(1H, m), 4.36(2H, 1127, 1030, 956 s), 6.49(1H,s), 6.57(1H, brs), 7.14-7.22(1H, m), 7.23-7.32(4H, m), 7.69(1H, brs) 1053417, 2944, 2592, 1.46-1.62(2H, m), 1.70-1.95(2H, m), 2.01-2.22(2H, m),1664, 1595, 1496, 2.09(3H, s), 2.14(3H, s), 2.18(3H, s), 2.76-3.01(2H,1418, 1371, 1321, m), 2.83 & 2.90(3H, each s), 2.92(2H, s), 3.27(3H, s),3.33 1285, 1142, 1129, (2H, brs), 3.74 & 4.39(1H, m), 4.54 & 4.56(2H,each s), 1103, 1033 6.52 & 6.56(1H, each s), 7.19(2H, t), 7.29-7.37(1H,m), 7.41 (2H, t) 106 3423, 1664, 1605, 0.81, 0.95 & 1.20(3H, m),1.50(3H, d), 1.58(2H, m), 1544, 1485, 1462, 1.66(1H, m), 1.92(2H, m),2.11(3H, s), 2.12 & 2.13(3H, s), 1386, 1324, 1116, 2.17(3H, s), 2.19(2H,m), 2.33-2.37(1H, m), 2.46-2.51 1034, 953 (1H, m), 2.90(2H, m), 3.38(2H,brs), 3.83(1H, m), 4.44 (1H, q), 6.47(1H, s), 6.52(1H, m), 7.03(2H, d),7.13 (1H, t), 7.21-7.26(2H, m) 107 3426, 2943, 1684, 1.40-1.88(4H, m),1.56 & 1.57(6H, each s), 2.00-2.32(1H, m), 1619, 1552, 1518, 2.07, 2.08,2.10, 2.15 & 2.17(15H, each s), 2.47(1H, t), 1466, 1411, 1157, 2.86 &3.14(3H, each s), 2.85-3.10(2H, m), 3.10 & 3.16(2H, 1089, 872 each s),3.34(2H, brs), 4.57 & 4.77(1H, m), 5.35(1H, brs), 6.32 & 6.37(1H, eachs), 6.55(1H, s), 7.48 & 7.50(1H, each s), 8.85(1H, brs) 108 3417, 2934,1668, 1.45-1.65(2H, m), 1.84-1.93(2H, m), 2.08-2.23(2H, 1595, 1544,1496, m), 2.11(3H, s), 2.15(3H, s), 2.16(3H,.s), 2.77(2H, m), 1454,1372, 1285, 2.92(2H, s), 3.27(3H, s), 3.39(2H, brs), 3.85(1H, m), 1240,1129, 961 4.34(2H, s), 6.48(1H, s), 6.53(1H, brs), 7.19(2H, d),7.30-7.37(1H, m), 7.41 (2H, m) 109 2565, 1720, 1650, HCl salt in DMSO-d₆& CDCl₃: 1.78(2H, m), 2.08-2.44(2H, m), 1498, 1456, 1422, 2.14(6H, s),2.28(6H, s), 2.77-3.04(2H, m), 2.81 & 2.90 1396, 1201, 1007, (3H, eachs), 3.25(1H, dd), 3.44-3.69(2H, m), 3.77-3.90 949, 799 (1H, m), 3.82(2H,s), 4.26(1H, dd), 4.72(1H, m), 7.32 (5H, m) 110 1646, 1497, 1456, 1.67 &1.78(2H, d), 2.10-2.50(16H, m), 2.77 & 2.80 1418, 1309, 1118, (3H, eachs), 2.96(1H, m), 3.06(1H, m), 3.34(2H, m), 1005, 945, 3.79 & 4.57(1H,m), 3.98 & 4.13(2H, each s), 4.26(2H, m), 752, 704 7.45(3H, m), 7.65(2H,m), 11.4 & 11.5(1H, s) 111 3426, 2940, 1692, 1.75 & 1.83(2H, m),2.20(6H, s), 2.24(6H, s), 2.20-2.32 1651, 1597, 1450, (2H, m), 2.81 &2.84(3H, each s), 3.27-3.43(2H, m), 1392, 1307, 1263, 3.60(2H, m), 3.93& 4.51(2H, m), 4.60(1H, m), 1233, 1153, 1109 5.03 & 5.07(2H, each s),7.63(2H, m), 8.00(2H, m) 112 3418, 2947, 1650, 1.71 & 1.83(2H, m),2.18(6H, s), 2.22(6H, s), 2.18-2.23 1500, 1454, 1415, (2H, m), 2.79 &2.81(3H, each s), 3.09-3.19(4H, m), 1312, 1201, 1153, 3.72(2H, m), 3.90& 4.08(2H, each s), 4.59(1H, m). 1106, 1069, 1029 5.18(1H, m),7.32-7.43(5H, m) 113 3418, 2948, 1647, 0.40(2H, m), 0.63(2H, m),1.11(1H, m), 1.69 & 1.81(2H, d), 1458, 1420, 1311, 2.10-2.40(4H, m),2.79 & 2.81(3H, each s), 3.15-3.80 1280, 1202, (4H, m), 3.55(2H, t),3.82 & 4.58(1H, m), 3.94 & 4.10 1100, 1064, (2H, each s), 10.87(1H, brs)1031, 950 114 3448, 1638, 1603, 1.67 & 1.80(2H, d), 2.19 & 2.22(12H, s),2.30-2.50(2H, m), 1508, 1373, 1308, 2.77 & 2.80(3H, each s),2.90-3.30(2H, m), 3.42(2H, d), 1263, 1193, 1110, 3.82 & 4.59(1H, m),3.92 & 4.08(2H, each s), 4.47 & 1070, 1008, 4.50(2H, each s), 11.95(1H,brs) 949, 798 115 1708, 1654, 1418, 1.67 & 1.78(2H, d), 2.10-2.40(14H,m), 2.77 & 2.80(3H, 1272, 1182, 1108, each s), 2.90-3.10(1H, m),3.10-3.30(1H, m), 3.30-3.50 1067, 1020, 1005, (2H, m), 3.77 & 4.57(1H,m), 3.97 & 4.12(2H, each s), 944, 871, 755 4.30-4.60(2H, m), 7.77(2H,t), 7.90-8.10(2H, m), 11.42 & 11.52(1H, brs) 116 3412, 2937, 1652, freebase in CDCl₃: 1.50-2.20(6H, m), 2.12(6H, a), 2.27 1568, 1422, 1394,(6H, s), 2.75 & 2.90(3H, each s), 2.85-2.95(2H, m), 1308, 1118, 1104,3.32 & 4.54(1H, m), 3.53(2H, d), 3.59(2H, d), 7.40(2H, t), 943, 8697.76(2H, d) 117 3397, 2951, 2748, 1.68 & 1.80(2H, d), 2.00-2.40(12H, m),2.77 & 2.80 1648, 1584, 1460, (3H, each s), 3.00-3.50(4H, m), 3.55(2H,t), 3.78(2H, q), 1422, 1310, 1155, 3.83 & 4.59(1H, m), 3.95 & 4.12(2H,each s), 10.47(1H, brs) 1080, 960 118 1730, 1659, 1643, 1.68 & 1.80(2H,d), 2.00-2.04(14H, m), 2.78 & 2.80 1581, 1496, 1424, (3H, each s),2.85(2H, m), 2.98 & 3.17(2H, m), 3.23( 1378, 1312, 1221, 2H, brs),3.48(2H, brs), 3.83 & 4.58(IH, m), 4.03 & 4.20 1071, 1035, 950, (2H,each s), 11.12(1H, brs) 866, 801 119 1646, 1629, 1496, 1.75 & 1.87(2H,d), 2.10-2.40(14H, m), 2.77 & 2.79 1456, 1361, 1308, (3H, each s),3.40-4.10(12H, m), 4.62(1H, m), 1277, 1092, 11.01 & 11.36(2H, s) 960,917 120 3424, 2940, 1652, 1.63-1.73(2H, m), 2.11-2.33(2H, m), 2.21(6H,s), 2.24 1456, 1366, 1298, (6H, s), 2.70 & 2.72(3H, each s), 2.76 &2.79(3H, each s), 1245, 1160, 2.96-3.09(4H, m), 3.23(2H, m), 3.57(2H,m), 3.80(2H, s), 1105, 1066 4.55(1H, m), 7.24-7.29(3H, m), 7.33-7.37(2H,m) 121 2942, 2710, 1656, free base in CDCl₃: 0.09(2H, m), 0.51(2H, m),0.85(1H, m), 1642, 1462, 1453, 1.20 & 1.27(3H, each d), 1.42-2.30(8H,m), 2.09(3H, s), 1416, 1311, 2.10(3H, s), 2.23(3H, s), 2.25(3H, s), 2.69& 2.77(3H, 1250, 1075, each s), 2.96 & 3.11(2H, m), 3.19 & 4.48(1H, m),1033, 948 3.40(2H, brs), 3.94(1H, m) 122 2937, 2690, 1646, 1.21 &1.28(3H, each d), 1.45-1.98(4H, m), 2.05-2.23 1493, 1456, 1314, (2H, m),2.09(3H, s), 2.11(3H, s), 2.23(3H, s), 2.25(3H, s), 1247, 1072,2.50-2.05(2H, m), 2.70 & 2.78(3H, each s), 2.72-2.92 1031, 1015 (2H, m),3.05(2H, m), 3.24 & 4.50(1H, m), 3.40(2H, brs), 3.94(1H, m),7.13-7.30(5H, m) 123 3376, 2936, 2714, 1.48-1.64(2H, m), 1.97-2.06(2H,m), 2.11(6H, s), 2.19- 1075, 1500, 1450, 2.29(2H, m), 2.23(6H, s),2.57-2.05(2H, m), 2.70-2.90 1310, 1282, 1252, (2H, m), 2.93(2H, m),3.45(2H, s), 3.49(2H, brs), 3.92 1142, 1115, (1H, m), 7.17-7.33(5H, m)1067, 950 124 3443, 2959, 2716, 1.60-2.10(4H, m), 2.10-2.30(2H, m),2.19(6H, s), 1052, 1450, 1364, 2.24(0H, s), 2.50-2.70(2H, m),2.70-2.80(2H, m), 1313, 1283, 2.76 & 2.80 & 2.90(9H, each s), 3.00 &3.09(2H, d), 1162, 1018, 3.32 & 4.55(1H, m), 3.68 & 3.71(2H, each s)758, 705 125 2937, 2717, 1640, 1.42-2.06(6H, m), 2.12(3H. s), 2.18(3H,s), 2.25(3H, s), 1577, 1489, 1451, 2.77 & 2.90(3H, each s),2.98-3.62(6H, m), 3.32 & 4.58 1334, 1300, 1284, (1H, m), 3.69 & 3.72(2H,each s), 6.20-6.38(1H, m), 1153, 1109, 1029, 6.53(1H, m), 0.74 &6.75(1H, each s), 7.20-7.28(1H, 978, 944 m), 7.32(2H, m), 7.35-7.42(2H,m) 126 2946, 2751, 1650, 1.47-2.35(6H, m), 2.12(3H, s), 2.19(3H, s),2.24 & 2.25 1599, 1491, 1242, (3H, each s), 2.28-2.44(2H, m), 2.77 &2.90(3H, each s), 1154, 1110, 1079, 2.94-3.20(2H, m), 3.33 & 4.57(1H,m), 3.49(2H, brs), 1042, 947, 762 3.70 & 3.73(2H, each s), 3.98(2H, d),4.03-4.18(1H, m), 6.74 & 6.76(1H, each s), 6.89-7.00(3H, m), 7.24-7.33(2H, m) 127 3425, 2935, 2562, 1.38-2.35(OH, m), 2.12(3H, s), 2.19(3H,s), 2.24 & 2.25 1693, 1648, 1597, (3H, each s), 2.77 & 2.90(3H, each s),3.03-3.15(2H, m), 1488, 1451, 1394, 3.34 & 4.57(1H, m), 3.38-3.62(2H,brs), 3.70 & 3.73(2H, 1306, 1262, 1232, each s), 3.84 & 3.85(2H, eachs), 6.74 & 6.76(1H, each s), 1107, 1078, 7.47(2H, m), 7.58(1H, m),7.98(2H, m) 952, 759 128 2936, 2573, 1646, 1.45-1.83(4H, m), 2.12(3H,s), 2.17 & 2.18(3H, each s), 1618, 1575, 1469, 2.23 & 2.25(3H, each s),2.76 & 2.89(3H, each s), 3.14 1448, 1324, 1279, (1H, m), 3.49(2H, brs),3.56 & 4.78(1H, m), 3.71 & 3.75 1130, 1022, 788 (2H, each s), 3.89(1H,m), 4.49(1H, m), 4.85(1H, m), 6.74(1H, s), 7.41(5H, m) 129 3424, 2593,1638, 0.02-0.17(2H, m), 0.45-0.56(2H, m), 0.85(1H, m), 1.46-1.82 1573,1490, 1404, (4H, m), 1.84-2.31(4H, m), 2.12(3H, s), 2.19(3H, s), 1360,1312, 1281, 2.25 & 2.26(3H, each s), 2.76 & 2.90(3H, each s), 3.07-3.211201, 1107, (2H, m), 3.29 & 4.51(1H, m), 3.49(2H, brs), 3.69 & 3.721031, 948 (2H, each s), 4.37-4.61(1H, m), 6.74 & 6.75(1H, each s) 1302933, 2852, 1656, 1.46-1.70(2H, m), 1.72-1.85(2H, m), 2.11(3H, s),2.15(3H, s), 1648, 1584, 1486, 2.21(3H, s), 2.72 & 2.84(3H, each s),3.38-3.54(2.5H, m), 1447, 1333, 1307, 3.59 & 3.67(2H, each s), 3.91(2H,m), 4.42(1.5H, m), 1167, 1094, 1024, 6.71 & 6.72(1H, each s), 7.55(2H,t), 7.63(1H, t), 936, 740 7.70(2H, d) 131 2937, 2727, 1648,1.48-2.28(6H, m), 2.11(3H, s), 2.18(3H, s), 2.23 & 2.24 1489, 1455,1420, (3H, each s), 2.75 & 2.89(3H, each s), 2.94(2H, m), 1309, 1105,3.29 & 4.38-4.60(2H, m), 3.50(4H, m), 3.68 & 3.71(2H, 1031, 946 each s),6.73 & 6.75(1H, each s), 7.20-7.35(5H, m) 132 3444, 2938, 2878, 0.91(3H,t), 1.23-1.38(2H, m), 1.40-1.51(2H, m), 1.64-1.95 1638, 1572, 1484, (2H,m), 1.98-2.38(4H, m), 2.12(3H, s), 2.18(3H, s), 1424, 1406, 1361, 2.24 &2.25(3H, each s), 2.75 & 2.86(3H, each s), 2.93- 1317, 1202, 1094,3.06(2H, m), 3.28 & 4.39-4.59(2H, m), 3.49(2H, m), 1015, 946 3.69 &3.72(2H, each s), 6.74 & 6.75(1H, each s) 133 2930, 2726, 1646,1.47-1.63(2H, m), 1.67-1.81(2H, m), 1.82-2.07(2H, m), 1571, 1486, 1420,2.11(3H, s), 2.18(3H, s), 2.23 & 2.24(3H, each s), 2.76 & 1337, 1306,1106, 2.90(3H, each s), 2.99(2H, m), 3.31 & 4.36-4.62(2H, m), 1030, 942,826 3.47(2H, brs), 3.65(2H, s), 3.68 & 3.71(2H, each s), 6.73 & 6.74(1H,each s), 7.42-7.52(3H, m), 7.73-7.80 (1H, m), 7.81(3H, m) 134 2942,2818, 1634, 1.45-1.88(4H, m), 2.12(3H, s), 2.17 & 2.18(3H, each s),1488, 1430, 1332, 2.25(3H, s), 2.77 & 2.89(3H, each s), 3.17 & 4.47(1H,m), 1273, 1252, 1168, 3.38-3.85(4H, m), 3.71 & 3.75(2H, each s),4.79(2H,m), 1128, 1073, 6.72 & 6.74(1H, each s), 7.59(2H, m), 7.69(2H,m) 1023, 816 135 3440, 2954, 1618, 1.44-1.84(4H, m), 2.21(3H, s),2.26(3H, s), 2.27(3H, s), 1576, 1448, 1371, 2.72-2.93(2H, m), 2.78 &2.79(3H, each s), 2.81(6H, s) 1323, 1280, 1129, 3.13 & 4.57(1H, m),3.40-3.64(2H, brs), 3.68-3.93(2H, m), 1115, 1021, 790 4.78(2H, m),6.78(1H, s), 7.41(5H, brs) 136 3426, 2940, 1654, HCl salt in DMSO-d₆:1.71 & 1.90(2H, m), 2.09 & 2.11(3H, 1514, 1454, 1415, each s), 2.18(3H,s), 2.28(2H, m), 2.79 & 2.93(3H, each s), 1390, 1310, 1246,3.07-3.17(4H, m), 3.26(2H, m), 3.57-3.63(2H, m), 3.97 & 1221, 11014.08(2H, each s), 4.60(1H, m), 6.65 & 6.69(1H, each s), 7.03(1H, s),7.27-7.35(5H, m) 137 3426, 2940, 1639, HCl salt in DMSO-d₆:1.09-1.17(2H, m), 1.45(1H, m), 1514, 1498, 1461, 1.69 & 1.89(2H, m),2.11(3H, s), 2.17 & 2.18(3H, each s) 1414, 1303, 1248, 2.24-2.40(3H, m),2.78 & 2.92(3H, each s), 3.05-3.17 1095, 1030 (4H, m), 3.54(2H, m), 3.96& 4.07(2H, each s), 4.58(1H, m), 6.65 & 6.68(1H, each s), 7.01(1H, s),7.17(3H, m), 7.28(2H, m) 138 3378, 2936, 2630, 1.67-1.97(2H, m),2.20(2H, m), 2.78 & 2.90(3H, each s), 1641, 1518, 1413, 3.08(4H, m),3.28(2H, m), 3.40-3.57 & 4.56(1H, m), 1308, 1202, 1098, 3.65(2H, m),3.95 & 4.05(2H, each s), 6.79 & 6.84(1H, each s), 1074, 755 7.14 &7.15(1H, each s), 7.21-7.41(5H, m), 10.43(1H, brs) 139 3444, 2942, 2596,1.72 & 1.86(2H, m), 2.18(2H, m), 2.78 & 2.80(3H, each s), 1692, 1637,1556, 3.29(2H, m), 3.59(2H, m), 4.09 & 4.16(4H, each s), 4.58 1488,1448, 1405, (1H, m), 7.08-7.15(3H, m), 7.36(2H, t). 7.62(2H, m) 1346,1302, 1153,

The effects, such as cytoprotective effect against glutamate inducedcell death using neuron of cerebral cortex, calbindin D28Kd inducingeffect by the western blot technique, and cerebral edema suppressingeffect of aminophenoxyacetic acid derivatives, of the formula (I) havebeen evaluated by following biological testing methods.

Biological Test 1: Cytoprotective Effect Against Glutamate Induced CellDeath

In accordance with the method of M. P. Mattoson [M. P. Mattoson, BrainRes. Rev., 13, 179 (1988)], brain of 18-days fetus rats of Wister strainwere taken out. Then, cells of cerebral cortex (4×10⁵ cells/ml) wereseeded on poly-L-lysine coated 96 wells flat bottom plate (SumitomoBakelite Co., Ltd.) in concentration of 4×10⁴ cells/each well. After 48hours of incubation, 1 μM of test compounds were added, then afterfurther 24 hours, 1 mM of glutamate were further added for inducing thecell injury. 12 hours after adding glutamate, MTT[3-(4,5-dimethylthiazol)-2,5-diphenyltetrazolium bromide] was added andincubated for 6 hours.

After incubation, 200 μl of dimethy sulfoxide was added to each wells,and the amounts of reduced MTT were calorimetrically analyzed by MicroELISA Reader using 570 nm of main-wavelength and 650 nm ofsub-wavelength.

The effect of the test compounds was determined as the survival rate ofliving cells (%) according to the following equation:Survival rate of living cells (%)=[(test compound group−glutamatetreated group)÷(control group−glutamate treated group)]×100

That is, the survival rate of living cells after incubation of thecontrol group was converted to 100%, and the survival data of livingcells of the tested compounds was shown in Table II.

TABLE II Survival Rate Compound (%) No. (Compound: 1 μM) 38 114 40 10841 86 42 131 44 93 45 190 46 101 48 207 49 193 50 54 53 144 60 60 61 5862 63 65 73 66 60 67 69 68 75 69 68 70 88 71 89 74 87 75 96 76 106 77111 78 96 79 79 80 99 81 97 82 149 83 65 84 87 85 98 86 127 87 81 88 8189 126 90 149 91 203 92 66 93 171 94 198 95 61 96 91 97 119 98 120 99151 100 138 101 138 102 89 103 180 104 117 105 86 106 151 107 227 109 76110 61 111 84 112 76 113 74 114 50 116 59 119 115 120 88 121 82 124 86125 52 126 47 127 72 128 81 129 64 130 60 131 65 132 60 133 101 134 79135 76 136 81 137 71 138 42 139 53

Biological Test 2: Calbindin D28Kd Inducing Effect

In accordance with the method of M. P. Mattoson [M. P. Mattoson, BrainRes. Rev., 13, 179 (1988)], brain of 18-days fetus rats of Wister strainwere taken out. Then, cells of cerebral cortex (5,500 cells/m²) wereseeded on poly-L-lysine coated 6 wells plate (Falcon) (3.5 mm, Sumilon)and incubated for 7 days.

Test compounds were added on culture day 5, and after 7 days ofincubation, the protein was extracted with homogenized buffer-solution[containing 20 mM of Tris-HCl (pH=7.4), 1 mM of EDTA, and 0.1 mM ofphenylmethylsulfonyl fluoride].

The effect of the test compounds was determined by the western blottechnique using polyclonal anti calbindine D28K (Swant Co., Ltd.) asantibody.

Table III shows the test results. In the table, the amount of inducedcalbindine D28Kd of the control group (none-treated group) was indicatedas 100 percents.

TABLE III Amount of induced Calbindine D28Kd Compound (% vs. control)No. (Compound: 1 μM)  29 122  40 150 111 167 128 171 Control 100

Biological Test 3: Cerebral Edema Suppressing Effect

8-week-old rats of slc:Wister strain were used. Rats were anesthetizedby intraperitoneal administration of 50 mg/kg of Nembutal (Trade Name),and then, fixed on brain fixactor. The sterile metal screw (3.75 mm inlength/1.0 mm in diameter/0.75 mm in length of screw thread) was pluggedin the 1.5 mm right and 0.8 mm rear side of the bregma to pressfrontparietal cortex organ to cause brain injury.

6 days after the operation, the whole brain was taken out and rightcerebral hemisphere (injured side) was isolated. After measurement ofthe wet weight of the cerebral hemisphere, it was dried at 110° C. for24 hours on aluminum foil. The dry weight of the cerebral hemisphere wasmeasured, and the water content was calculated by using the followingformula:Water content (%)=[(wet weight of hemisphere−dry weight ofhemisphere)/wet weight of hemisphere]×100

The test compounds were intravenously administered just after theoperation via tail vein of the rats.

Table IV shows the test results.

TABLE IV Compound No. Cerebral edema (admintration amount) suppressingrate (%)  29 (3 mg/kg) 30.9  40 (1 mg/kg) 31.1  40 (3 mg/kg) 20.5  42 (1mg/kg) 24.5  42 (3 mg/kg) 31.0 104 (3 mg/kg) 18.9 105 (3 mg/kg) 23.2 108(3 mg/kg) 20.3 109 (3 mg/kg) 24.7 111 (3 mg/kg) 25.0 112 (3 mg/kg) 20.7113 (3 mg/kg) 20.0 119 (1 mg/kg) 21.6 128 (3 mg/kg) 20.3 132 (1 mg/kg)30.4 134 (1 mg/kg) 27.9 134 (3 mg/kg) 35.0

INDUSTRIAL APPLICABILITY

As described above, the present invention provides lower molecularweight compounds, especially aminophenoxyacetic acid derivatives of theformula (I), which is capable of inducing the calbindin D28Kd, one ofCa²⁺-binding proteins, and can be easily administered. Since theinduction of calbindin D28Kd caused by the administration of thecompound provided by the present invention cause neuroprotective effectand cerebral functional and organic disorder improving and treatingeffect, it can be understood that the agent of the present invention ishighly applicable in pharmaceutical field.

1. A composition comprising a compound which is4-({4-[[(4-Amino-2,3,5,6-tetramethylanilino)acetyl]-(methyl)amino]-1-piperidino}methyl)benzamideor a pharmaceutically acceptable salt thereof, in an amount effectivefor improving brain cell survival or suppressing cerebral edema, and apharmaceutically acceptable carrier therefor.
 2. A compositioncomprising a compound which is2-(4-Amino-2,3,5,6-tetramethylanilino)-N-[1-(cyclo-propylmethyl)-4-piperidinyl]-N-methylpropamide or a pharmaceutically acceptable saltthereof, in an amount effective for improving brain cell survival orsuppressing cerebral edema, and a pharmaceutically acceptable carriertherefor.
 3. A composition comprising a compound which is2-(4-Amino-2,3,5,6-tetramethylanilino)-N-methyl-[1-(2-phenyl-2-oxyethyl)-4-piperidinyl]acetamide or a pharmaceutically acceptable salt thereofin an amount effective for improving brain cell survival or suppressingcerebral, and a pharmaceutically acceptable carrier therefor.
 4. Acomposition comprising a compound which is2-(4-Amino-2,3,5,6-tetramethylanilino)-N-[1-[1-(2-hydroxy-2-phenylethyl)-4-piperidinyl]-N-methylacetamide or a pharmaceutically acceptable saltthereof, in an amount effective for improving brain cell survival orsuppressing cerebral, and a pharmaceutically acceptable carriertherefor.
 5. A composition comprising a compound which is2-(4-Amino-2,5-dichloroanilino)-N-[1-(2-phenethyl)-4-piperidinyl]acetamideor a pharmaceutically acceptable salt thereof, in an amount effectivefor improving brain cell survival or suppressing cerebral, and apharmaceutically acceptable carrier therefor.
 6. A compositioncomprising a compound which is2-(3-Amino-2,4,6-trimethylanilino)-N-(1-benzoyl-4-piperidinyl)-N-methylacetamideor a pharmaceutically acceptable salt thereof.